2022-06-09 - Interview Dr. David Sinclair - Tom Bilyeu - The DAILY HACKS To Look Younger, Live Longer & REVERSE YOUR AGE

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• Length: 1:47:41
• Interviewee: Dr. David Sinclair
• Interviewer: Tom Bilyeu

Transcript

Introduction to David Sinclair

0:00	so we're reversing aging of the eye that's not hard at all but we can reverse the age of the liver
0:05	or the skin other labs are doing the spleen thymus through this method

Daily Hacks to Slow Aging

0:12	what are the things that we can do today to slow aging so that we don't end up needing this or
0:19	so that we can live long enough that this goes through all the safety and all that and it becomes an actual actual just like
0:25	standard of care procedure well before we get into what we can do today just because it's a continuum of
0:32	this resetting what my lab and many others now are doing is racing to find easier ways to
0:38	reset the age of the body gene therapy it's here but it's not going to be you
0:44	know mainstream soon it's always going to be expensive hundreds of thousands of dollars of treatment what happens when you can take
0:51	a pill that will reset your age by a year happy birthday dad
0:56	take this pill incredible and if you reset your age by a year every year that's pretty interesting philosophy uh
1:03	and yeah and there are experiments now where people have reversed their dna methylation age which we can now measure
1:09	uh by a couple of years and that only takes a year so now people going back at least their bloodstream is
1:15	going back younger than that year took them forward wow so we are on the verge of something
1:21	super interesting in humanity it opens up all sorts of questions about what's the world going to look like for maybe
1:27	us certainly for our kids but getting back to what we can do every day
1:33	the main concept that i think we all need to remember is that our bodies respond well to
1:39	perceived adversity those of us who you know like to struggle in life i know
1:46	you're that kind of guy it's don't give up just keep going our bodies respond well to that as long as you're not doing long
1:52	lasting harm an adversity mimetic which can be
1:57	don't eat so much don't eat so often exercise be cold be hot there are some other tweaks to that
2:03	high pressure oxygen therapy is another theme these put the body in a state of
2:09	adversity mimicry and what that does to the bodies that says oh my goodness i could be dead next
2:15	week i could run out of food i could be you know chased down by that tribe over the hill or a saber-toothed tiger i
2:22	gotta hunker down and become more robust and don't put so much energy into
2:28	these other things you know maybe wound healing would be one thing you could take away from for a little bit
2:33	and put it into long-term survival those are the the roles of the sirtuins
2:39	remember the solutions do two things they slow down aging on the dna but they also go and repair things and if you
2:45	don't have enough so two an activity or enough sort of two and proteins in your body so in other words you don't make
2:51	enough of these little machines or the ones that you have are pretty inactive and lazy but don't have enough of the
2:56	fuel that they need to work then you're going to age more rapidly and when the crap hits the fan and you
3:03	get a broken chromosome then you're not going to have as much ability to repair that you might get cancer
3:09	and so what my role or my goal in in my lab and in my experiments with my body is to
3:16	make those processes that respond to adversity super active every day so that
3:22	it's slowing down the aging process until we have the technology to reset the body and reverse it
3:29	so i have a gas hypothesis on why that would work um because you've talked about like as
3:36	we get into mtor and some of your diet recommendations so
3:43	basically there are things like getting into mtor which is growth if you want to add muscle you're gonna have to get into mtor you're gonna have to give your body
3:50	the signal to grow which times are good there isn't these you know adverse things um and great if you're young
3:57	great if you're trying to put on muscle but it may have these long-term consequences versus putting your body into this
4:04	actually things are hard now is not the time let's dial back
4:09	let's make sure that we stay strong and my gut instinct is that from an evolutionary standpoint that would be a
4:15	mechanism designed to make sure that you live long enough for times to return to good so that you can procreate
4:22	and that you're sort of going into like a semi-hibernation to like la outlast
4:29	whatever environmental problem there is so that you can
4:35	still be around when the environment changes does that ring true for why this mechanism works
4:41	it does except hibernation gives the impression that you don't have as much energy right and that's not true that
4:46	wasn't going to be the right word yeah not true people who do what i do have way more energy than someone who sits around and
4:52	doesn't exercise and eats too much and our bodies rev up and make more energy so that we can repair the body we
4:59	need that energy to fix the dna and get rid of the old proteins and survive
5:04	so think of it as hunkering down but but also having more energy to be able to survive anything that comes at you
5:12	and so the converse to adversity mimetics which is what i try to do are the abundance mimetics so you
5:19	mentioned mtor mtor will sense if you're eating a steak lots of amino acids great build new muscle that's going to work
5:25	but an adver abundance memetic is not going to make you live longer we
5:31	know that you can manipulate this mtor uh enzyme complex we call it let's call
5:36	it a gene the mtor gene you can manipulate that in a mouse and give it less or more of
5:42	the mtor activity and when you do that their lifespan changes
5:47	and the more you have of it let's say you've now made it like the mouse is full of abundance it'll live short
5:53	and vice versa it'll live longer if you turn down the activity of that gene
5:59	and you can do that i mean we can't genetically engineer ourselves easily these days and i say easily you can but not easily
6:07	but what you can do is by eating things that are right you can make mtor believe that there's adversity and turn on the
6:14	repair systems all right so what does this adversity memetic look like from a
6:20	lifestyle perspective so you rattled off a few things really fast but i imagine um
6:26	diet and exercise are probably going to be two of our most important things and then knowing some of your views on supplements i think we should get into
6:32	that as well right well i do talk a lot about the tweaks on exercise and diet but been
6:39	in a very scientific and detailed way sometimes i feel a bit silly saying oh diet and exercise like why is this guy
6:46	who studies the process of aging and the molecular basis of it talking about these
6:52	diet and exercise we've known that for decades but what we haven't known is how they work we just discovered that just
6:58	by looking at thousands of people who live long and who don't and okay eat that diet
7:03	fast that time do that kind of exercise we know those people live longer but we didn't know why so now we do so we can tweak it we
7:10	can maximize the benefit of those lifestyle changes but it's worth pointing this out because
7:16	i think it's it's empowering so point one is we can measure our biological age we can look at the dna
7:22	methylation we can look at our bloodstream i do that and some people don't do that because they're scared of learning their
7:27	biological age what if it's too high what am i going to do but information knowledge is power
7:34	and the important point number two is that 80 percent of your longevity in your
7:39	health in old age is controllable and only 20 is dictated by your genes the re the genome the rest
7:46	is the epigenome that responds to how we live so that's why i'm all gung-ho for for
7:51	changing your lifestyle because it's gonna it could give you two more decades of life and i'm not kidding if you just
7:57	do the five things that doctors recommend typically don't smoke don't over drink get enough sleep get a bit of
8:03	exercise and don't be overweight if you do that versus someone who doesn't you live on average 14 years
8:10	longer and that's just the stuff we know of but there gets to be some really interesting stuff that is just now at
8:17	least making my level of awareness and i think that some of this speaks to this
8:24	idea of the um adversity memetic so
8:29	when you pointed out that a type 2 diabetic so diet induced lifestyle
8:36	induced diabetes is going to live longer
8:42	than somebody without diabetes if they're taking metformin
8:48	that's insane to me here's my hypothesis and you'll tell us whether this makes any sense so
8:53	insulin seems like the problem child here and so by elevating my glucose levels i have to pump all this insulin
9:00	into the system the insulin is potentially damaging things somehow some way i don't understand the mechanism but
9:06	it's over abundant presence causes damage to the cells in some way shape or
9:11	form by taking metformin it's keeping my blood
9:16	glucose levels down which means that it's going to keep my insulin levels down and therefore i
9:22	wouldn't be doing the damage to the system so even though i may be in taking the things that turn into glucose
9:28	because of the use of metformin i'm actually keeping my insulin response down so therefore i never get that thing
9:34	that ends up damaging the system and therefore even though i started as a type 2 diabetic and that's why i'm on
9:41	the metformin because of its impact on insulin i never get the damage isn't occurring at the
9:47	level that it would even for somebody who is not a diabetic does that sound about right
9:54	kind of kind of let's go back to what is metformin metformin is a derivative of
10:00	plant molecule that inhibits the cell's ability slightly to make energy and in response so it's an
10:07	accuracy on the mitochondria yes so mitochondria in high school we
10:12	were taught that the power packs of the cell they do a lot more they make amino acids that make fat they do all that
10:17	stuff but we need them for energy without mitochondria we're dead again in 30 seconds
10:22	um and the way and so i'm drawing this because they're like little bacteria in our cells they float around and they make energy for us in fact
10:30	like four billion years ago uh actually only one billion years ago uh mitochondria were free-floating bacteria
10:36	that were subsumed by us it's crazy so we have little pets in our body and they have their own dna
10:42	uh which does get mutated over time the reason metformin seems to work one of
10:49	them is that it inhibits the ability of mitochondria to make the energy so mitochondria are like a hydroelectric
10:55	dam there's water but in this case it's hydrogen atoms not water that gets
11:01	pumped into a reservoir which is between two membranes on the outside of the of the the bubble of the bacterium
11:08	thing so now hydrogen atoms are really acidic that's what acid is lots of hydrogen protons and when you get a lot of
11:15	something it likes to equilibrate remember that you go from a lot too little it flows
11:21	but there's a membrane in between from the high level to the low level in so internal is low high is outside and the
11:28	cell puts this little uh generator in between that outside space in the inner space
11:35	uh the outer membrane space and the inner membrane so this is what we call it and this little little power generator
11:41	sits there and those protons shoot through a pore in that protein
11:46	and at the bottom is a is a generator it spins literally if the protein is spinning at thousands of times per second oh and
11:53	as it's spinning it's doing a chemical reaction to make what's called atp
11:59	adenosine triphosphate doesn't matter its name that atp is chemical energy that we use
12:04	to to live to make things to grow and so what metformin does is that it
12:09	reduces the the ability of cells to uh make that uh those proton gradients it's called
12:17	and so you don't build up as much power and you don't make as much atp initially with glucose why do you give
12:24	that to a diabetic what is up my friends i have huge news for you about one of the most exciting and important projects
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13:34	friends be legendary take care peace well what happens is
13:39	that there's a process called mitochormesis hormesis is adversity what doesn't kill
13:46	you makes you stronger and mido is the mitochondria are experiencing adversity or perceived adversities the
13:51	mitochondria are freaking out i can't make enough energy i don't have enough enough atp
13:57	okay and what gets activated is a protein called ampk ampk
14:03	is a regulator of energy in our bodies that senses when we don't make enough energy
14:08	and what metformin does is it comes in and it activates that ampk step and now the cells are freaking out
14:16	that they're not making enough energy and in response they'll make more
14:22	and so you have a little drop in energy temporarily when you take a pill but then the cell rebounds and starts
14:27	making a lot more energy and you actually mitochondria will multiply you get more of these little bacteria
14:33	in your cells so taking metformin causes a replication of your mitochondria yeah
14:39	okay ampk starts but i still don't know how this ties into glucose
14:44	well when you when you activate ampk you don't just make more mitochondria but cells start to put out a new protein
14:52	that we haven't talked about new to this chat are called glute4 and that stands
14:57	for glucose transporter number four and it goes to the outside of the cell right on the very what we call plasma
15:04	membrane and it sits there and now its job is to suck the glucose out from the liquid around so it's no longer waiting
15:10	for insulin to come around to push the glucose into the cell it's like yo
15:15	i need glucose to help with this energy creation
15:20	it does and it so it makes more of this protein but it also becomes what we call insulin sensitive so the
15:26	little bit of insulin that you have around if you're a type 2 diabetic works better
15:32	okay you get more insulin receptor which is the protein that senses insulin so all in all what happens to that cell
15:37	just to summarize because it's a bit complicated is that by tricking the cell into thinking it doesn't have enough
15:43	energy it panics adversity hormesis and it'll go now and put the protein on
15:49	the surface to grab the glucose and be more sensitive to the hormone insulin that tells the cell to suck it in
15:56	why is that good because then your glucose levels in your bloodstream will come down and you're no longer type 2 diabetic
16:02	there are two reasons i believe why being type 2 diabetic accelerates aging why you don't want to have high levels
16:07	of glucose and why i try to keep my mind you think insulin is is irrelevant in this chain
16:12	i do it's a signaling molecule okay um i mean over time your pancreas will suffer because it has to make more and more of
16:19	it but that's not what's aging your brain and your muscle and all these other things what's going on is two things
16:24	one is that that glucose will attach to proteins all the time it just sticks to it and in
16:31	fact the diagnosis of type 2 diabetes is to look at an abundant protein in your body in your blood that you can access
16:36	at your doctor's office and figure out what percentage of that protein is stuck to glucose
16:43	and that's hemoglobin in your red blood cells and if you've got five percent or less hemoglobin attached
16:51	uh to the glucose you're healthy and then you get 6.5 you're pre-diabetic and
16:56	higher than that you're heading towards type 2 diabetes and that's just all about glucose attaching to proteins
17:02	and glucose attaching to proteins messes things up and they can really not work well but
17:08	that's really not the root cause of aging as i've told you what's also going on is that the high
17:13	levels of glucose are making your cells complacent tons of energy got lots of
17:19	this stuff going around the hormones your brain thinks that it's good you're swimming in treacle
17:24	and so your adversity and repair systems the sirtuins they don't work as hard and so your clock is
17:31	ticking faster that's why type 2 diabetics have other they don't work as hard or they're lumbering under the weight of glucose that's stuck to them
17:38	interestingly both so tunes will get attached to sugar but they also they don't
17:45	turn on like they get attached to sugar or sugar gets attached to them sugar gets attached to them okay yeah
17:53	but what's also a real problem is that that adversity system is complacent
17:59	and so by keeping your glucose levels down even at a young age well i'm not
18:04	young but even at a young age your your body will be in this adversity
18:09	state versus abundance and that can explain why type 2 diabetics
18:15	are older when you measure it and also are susceptible to heart disease
18:22	dementia and even certain types of cancer and why metformin the drug that
18:27	keeps your glucose levels down and activates this mito hermesis defense doesn't just protect you against type 2
18:33	diabetes it by looking at tens of thousands of patients who that have taken metformin
18:38	they also have lower levels of heart disease dementia frailty and cancer
18:45	is bananas it is bananas do you take metformin i do
18:51	so i'm going to walk through what i think is your ideal protocol minus the supplementation i don't want to speak to
18:56	that i'll let you add any of that other than metformin if you think there's something else people should do but
19:02	okay so a primarily vegetable diet and a big part of the reason that i think
19:08	that you recommend a primarily vegetable diet is because of this
19:13	adversity mimetic versus abundance mimetic and that because red meat is so
19:19	rich in amino acids it gives a signal to the body that we have an abundance we can
19:24	grow and so we we're rapid growth but we're also aging ourselves um so we want
19:30	to create this um that little bit of a stressor
19:35	by or i should say we don't want the signal that we have abundance
19:42	we obviously have to eat well for protein we're going to need to make sure that we're getting all the protein that we need and all of that and that you
19:49	advise in taking vegetables that have gone through a hormetic
19:56	trial themselves so like with the wine grapes that are highest in
20:02	resveratrol they're often dehydrated and ones that have fungus on them i guess really do
20:08	well because resveratrol i would imagine is part of their defense mechanism it is yeah uh and then so
20:15	any vegetables that have had sort of a hormetic push is going to be a good idea and you give a bunch of examples that
20:21	i've heard before like oranges i guess if you drive a nail into the bark of the tree like before harvest that that helps it's so
20:28	interesting um well olives and olive oil oleic acid oleic acid will activate sirtuins
20:34	resveratrol it's not a coincidence that we figured out these kind of foods are good for us separately but now we understand
20:40	probably how they're working too so yes you're right so far with my lifestyle utterly fascinating uh heat
20:46	exposure cold exposure um fasting that's one that we should
20:52	probably go into a bit of detail about so intermittent fasting being a big one i know that you're doing omad one meal a
20:58	day i'd ask what that meant the first time i heard it [Music] and you're doing that you're still in
21:05	taking a fair amount of calories i mean you're in good shape but you're not withering away so i
21:10	imagine that you're roughly [Music] taking in enough calories to hit
21:15	maintenance levels right but only in a single meal a day do you eat like because i i think you eat in a two-hour
21:21	window i'm not strict about it i have dinner and occasionally i break down i have a little bit of a snack in the afternoon
21:29	and occasionally as needed occasionally i have lunch with friends occasionally i have breakfast but my my best days i would say probably at
21:36	least five six days a week are not eating maybe more than a nut a few nuts or a
21:42	nibble of chocolate until dinner and then dinner is great but dinner is a big meal for me
21:48	how many calories in your dinner i don't know but i go to a restaurant and i'm eating multiple dishes i just don't eat dessert
21:55	i steal little bits but that's it i avoid sugar like it's the plague for the reason we just mentioned
22:01	[Music] okay so uh you advise people to do prolonged
22:06	fasting if they can you don't personally just because it sucks and it isn't fun and you live your life at a very high
22:11	level and so it gets difficult and i will second that a 24-hour fast for me is pretty easy anything beyond that my
22:17	performance begins to decline certainly my levels of enjoyment begin to decline rapidly i've done a five-day fast and
22:23	after day three it's like being sick for me at least as i've done it i'm sure i could optimize and do it better but
22:30	i have found that trying to perform at the level that i perform at just has not been possible even at three
22:35	days halfway through day two i'm like i am not as good as i would normally be i
22:41	don't have the patience for certain meetings that i might otherwise have so i have a very similar response to
22:47	fasting but i i'm my average when you take it over a week because i'm slightly
22:52	shorter on the weekends my average is about 17 and a half hours a day 365 days a year
22:58	some days it's 14 and other days it's 22. so it just depends on
23:04	the date but it ends up because i tracked it really religiously for a long time it ends up on average all things taken into consideration 17 and a half
23:11	hours a day um is there a sweet spot i'm similar
23:17	i think that's the sweet spot for for you and me there are sweet spots that are different for everybody some people like breakfast
23:24	and don't care for dinner but you want to be able to i'm actually more like that my last meal is at 1 15
23:29	p.m oh wow okay but what you've got now is after after lunch you go all through the
23:35	night you've got that extended period you want to use the night as a period of fasting because you're not thinking about food when
23:40	you're sleeping anyway but but also i'm wondering if you see this too or feel this
23:46	for a few weeks when i i started doing this in more intensely and actually skipping lunch
23:51	it was tough it's tough for everybody i think because we we've got ghrelin coming out and we we have to eat
23:57	something we're used to eating but after three four weeks i didn't i didn't feel like eating in
24:03	fact if i ate something i'd get a little bit woozy or brain fog and what i saw when i was measuring it
24:09	so i've done uh the levels health thing on my arm so there's a glucose monitor continuous
24:15	glucose monitor on the phone that when you start your bodies doesn't know what to do
24:20	hungry you're losing glucose you feel tired you're hungry but what happens over time after three
24:26	weeks is you steady out and your liver wakes up and learns that it needs to do
24:31	a job its job which is in part making sugar for your body glucose but
24:36	our livers are much smarter than our eyes and our mouths much and and continuous your liver my liver
24:42	if you measure it during the day i showed you graph earlier when we were talking the the line through the day is really
24:48	steady in this zone and that's why i can power through the day i don't feel over energetic i don't
24:54	feel lethargic i don't even feel hungry but there's a really important point which is it's individual
25:00	the other important point is that you just you need to get through the hard part in the beginning yeah i don't think people
25:07	will believe you nor will they really understand what it means to become metabolically flexible so that you can
25:13	burn glucose or ketones and when you do it though it changes your relationship
25:18	to hunger it's not that i don't know that i'm hungry it's that it doesn't create any sense of urgency i'm not
25:24	distracted i'm not like oh my god i have to eat it's just oh yeah wow i guess i haven't eaten in a long time it and no
25:31	one will believe you until they've done it and i remember when i first went low carb and this wasn't even me quite going
25:36	keto but when i first went low carb i had a headache and i was so angry and i remember saying to my wife if i had a
25:41	cookie i would feel better and that was true it would have made me feel better but on the other side of that was
25:49	you finally break your metabolic dependency on sugar and now you can burn either glucose or ketones
25:56	because i used to measure my ketones all the time and i would i could predict
26:03	with pretty high degree of accuracy when i was over 0.5 when i was around one or
26:10	if i was north of one and because you feel differently it's pretty crazy yeah it's fun to do the glucose
26:16	monitoring because you can look on your phone and and you know how you feel
26:22	and i could very quickly see that if i ate normally like a normal uh american
26:28	a big breakfast huge spike in glucose goes up uh over 150 200 yep makes per deciliter and
26:36	i'm feeling wired and i've got caffeine in my body so okay i've got a couple of hours of
26:42	hyper and then i'd have this crash i'd feel terrible i need to go to sleep i didn't
26:47	sleep well enough i can't think i need to get a snack to get back to where i was
26:52	and then i look at my phone and i can see that i'm in this crash i've gone not just you know my levels are here i've
26:58	gone below that and now i'm feeling hungry i'm weak and then what do i do what does everybody do i get i need a snack i need
27:04	a protein bar or something and then shoot straight back up our days if on a normal meal a
27:12	normal american diet is like that yeah and it's highs and lows and highs like it's horrible horrible you've got to
27:17	break that cycle and just do the yeah and then you know a little bit in the evening food is required we're not
27:22	talking about salvation or malnutrition here right but tom the one thing i think is really important to tell everybody
27:28	who isn't doing this um is that i'm really lazy when it comes to life i really am it's surprising i've
27:34	gotten where i am i know the feeling and very well but what i i am pretty stubborn and i
27:41	like to do things to a point where at least i've satisfied myself that i can do something but i like meat i love meat i vegetables
27:48	for me were garnish for most of my life i love the taste of meat i would love if meat was life prolonging
27:55	i'd be the happiest guy but i've now learned a that that that vegetable at least plant focused you can
28:01	eat some meat and fish preferably it's not going to hurt you but
28:06	a carnivorous mainly carnivorous diet there's really no evidence that in the long run that's healthy unfortunately
28:13	so i've switched and i'm very happy with it i do enjoy a mostly plant-based diet now
28:20	exercise i freaking hate exercise i'm joe average or worse
28:25	i do not like the feeling of being out of breath at all i like lifting weights because at least
28:31	i don't lose my breath but i'm lazy i have to force myself to go to the gym every day
28:36	when i do it which isn't every day by the way so if i can do it
28:42	anybody should be able to do this it's just a matter of willpower and getting into the habit of doing that and letting
28:48	your body adjust talk to me about this notion of resetting the biological clock how do we

How to Reset Your Age

28:54	do that what's the mechanism and so obviously i'm going hungry occasionally exercise is going to help
29:00	but i know that you have a regiment that i'll lovingly call a regiment of drugs or precursors to things that we can take
29:07	what can we do to reset that biological clock well there are different levels to
29:13	resetting aging there are three levels that we know of the first is pretty easy to reset or to to manipulate these are
29:21	the proteins that turn genes on and off very quickly we call them transcription factors
29:26	and they they basically read a gene and make a protein that's what they do that's level one that's easy go a little
29:33	bit hungry that'll change level two is a little bit harder the level two is not just
29:38	changing which genes are quickly turned on and off but actually silencing genes for for a long time and
29:45	this is where my enzymes that we work on the sirtuins come into play let's go back to the pacman they clip
29:50	off acetyls off these packing proteins you spool up the hose and it becomes
29:55	becomes locked in that gene gets silenced for a long time so to do that
30:00	you can exercise you can diet but you also i think you need a little bit of help as well
30:06	what gets really interesting and this is something most scientists don't even know about yet is level three the deep layer of
30:13	aging there's actually a dna clock that tells our bodies how old we are we i could
30:19	take your blood and read it and i could tell you roughly when you're going to die what yeah we can do that what are you
30:26	looking for we're looking for chemical groups that get added and subtracted to our dna mole the long string in the cell
30:33	you get chemical modifications in predictable ways as you get older starting from conception so even in the
30:39	womb even as a kid even as a teenager you're aging based on this clock that goes up linearly and where you fit on
30:45	that line is very accurate that tells you your biological age but how do you know when
30:50	the person is going to die is that just based on straight lines is it actuarial tables
30:56	though the human average human lifespan is 86 and is that what you mean or is there could you see something specific
31:02	in my line that would say you're headed for 68 sorry
31:07	no it's not not specific but what it's based on is machine learning based on thousands of people's
31:14	code of methylation on the genome and comparing that to their health and their date of death oh [ __ ] that's so
31:20	interesting so if you were to take my blood right now what would you look for exactly we would read the methylation
31:26	the kemp these are chemicals hydrogen and oxygen bound to the dna chemically physically bound
31:32	and those accumulate as you get older in very predictable ways in fact they're so predictable
31:37	that we can use the same clock to measure the dog's age and a human's
31:42	age whoa all based on methylation right okay what causes methylation
31:48	well there are two classes of enzymes the ones that add the methyl chemicals and those that subtract it okay
31:55	how do i take a boatload of ones that subtract it ah that's what we're working on now here's the key level two aging reset
32:03	which we can do by some of the things that i'm doing in my life yeah probably you are too those aren't permanent changes you can't
32:09	just do that and expect that take take one treatment and you go on living for another 10 years okay because
32:16	level two isn't as permanent it's somewhat permanent than level one but level three is truly permanent it
32:24	you could reset yourself ten years and then go back and then wait another 10 years and potentially reset the clock
32:31	again if you know how to do that and we're just starting to figure out how to do that okay
32:36	so level one diet exercise cool got it level two uh metformin you taking metformin right
32:42	okay so i've talked about this on the show before but explain what is metformin why
32:48	is it prescribed to diabetics and now why is a seemingly rash of non-diabetic
32:53	people taking it yeah so there are three main pathways that regulate aging in animals and
33:00	probably in ourselves there are the sirtuins that i've talked about a lot today
33:05	there's one called mtor which responds to how much amino acids or how many amino acids are in your body it will
33:13	hunker down and protect the body the fewer amino acids it has access to okay okay then the third is called ampk
33:20	and this is the energy sensor when your body has low levels of energy it will allow the body to hunker down
33:27	and protect itself from diseases but why ampk is worth mentioning is this is one of the targets as we call it
33:34	of the drug metformin metformin will activate this ampk pathway and make the
33:39	body think that it's hungry when often it's not and also keep your blood sugar levels
33:45	more steady why would i uh hungry at a cellular level or i actually experience hunger at a certain level okay but it
33:52	also has an an interesting side effect is from for a lot of people myself included it's a bit harsh on the stomach
33:58	so it also reduces my appetite but what's great about metformin is that it's been in millions of people for a
34:04	few decades so we know the side effects they're relatively i'm sorry really fast so metformin is creating at a cellular
34:11	level the sense that i'm hungry and you're saying that from a hormesis perspective of a little bit of bad it's
34:16	like stressing the system and that's why we think it works it is it's exactly
34:21	doing that and so that it actually helps the body respond in a way to boost the energy supply uh so one thing it does
34:28	that's that's undeniable is it boosts the level the numbers of mitochondria it actually
34:34	creates additional mitochondria so your cells are getting more efficient or more able to generate energy
34:41	right over the long run but in the short run what it does is it actually poisons part of the mitochondria
34:47	so it's it's a little bit of poison that leads to benefits down the line what part is poisoned
34:53	uh it's called complex one so that there are protons that are
34:58	in one part of the area of the mitochondria in a in a membrane region and you the cell builds up protons it
35:04	becomes really acidic in that region but they the cell wants to release them so what they do is they put little pores
35:12	in between the membranes so they can leak from the high concentrated zone to the low concentration in the middle
35:18	and as they pass through that pore it spins the pore around and that
35:24	spinning physical spinning of that protein will generate chemical energy called atp
35:30	that's how atp is created and without atp we're dead in about 10 seconds yeah
35:35	okay that's crazy interesting uh and you're saying sorry to go back to the poison the poison is elevating those levels
35:41	which is causing more to go it's actually decreasing atp in the short run so the cell says man i haven't got
35:47	enough chemical energy in atp so that's what forces it to create more mitochondria right so that's the
35:53	poisoning part it is so the increased number of mitochondria is in response to the slight poisoning exactly but there
36:00	are two other important points the cells in our body also think that they need to become more
36:06	sensitive to insulin yeah which keeps our glucose and sugar levels more steady
36:11	okay yeah that's key because that's what helps the diabetes type 2 diabetics recover
36:17	and you know prevents the disease from getting worse yes the second is that it's just been discovered in humans that
36:23	if you take metformin a lot of it and exercise it can blunt the effects of exercise on building
36:29	mitochondria what we think is going on is that you don't want to always have metformin
36:35	in your system or your body won't have a chance to recover from that slight poison i'm not going to prescribe anything i'm
36:40	not a doctor but we think it's best better to take metformin on days that you're not exercising and
36:45	recovering and pulse it again so you've got metformin exercise metformin exercise right i know you're not prescribing
36:52	anything but uh how many days are you taking it how many
36:58	days you not how often are you exercising how often are you not um i actually spent a lot of my 30s and 40s not exercising at all it's crazy
37:05	right someone like me uh but i've become better at it now that i'm you know i was approaching 50 now
37:11	i'm 50. uh so i i spend uh about four hours in the gym on the weekend with my son
37:16	benjamin dude like two hours a day no four hours straight but it's not all exercise okay so it's an hour with my
37:23	trainer sean who does mostly a combination of weights and stretching um
37:29	some free weights some machines then it's another hour on my own with my son we do some treadmill some more
37:36	stretching and essentially just muck around doing stuff that's fun for him
37:41	and then we also then we do some some yoga downstairs in the gym a little
37:46	bit of relaxation but the best fun part that i really love is at the end we do a
37:52	sauna hot tub cold bath sauna hot tub cold bath for about an hour
37:58	and i feel fantastic talk to me about that so in your book you go into cold exposure you said you moved to boston it
38:03	sucked coming from australia and you bundled up and now you wish you hadn't um why cold exposure is cold and hot both
38:11	necessary what's the difference well there are a few reasons one is the high level view is that anything that
38:16	stresses your body puts it into a state of shock is good in the long run but a little bit of
38:22	perceived adversity being a little bit too hot a little bit too cold and especially the gradient between those
38:27	two which is why we jump from one to the other the next point is that i've looked at the literature
38:32	and at first when uh i was prompted by my publisher to look into this scientifically they said you know what
38:38	about this cryotherapy what do you think and a couple of years ago i had no idea that this was real it sounded like
38:44	[ __ ] to me but i looked into it and there were there are two important things one is cryotherapy or cold
38:50	exposure we'll build up what's called brown fat we didn't know brown fat existed in
38:56	humans until about five years ago typically it's across your back and in other reasons you can see with a pet scan but otherwise it's pretty invisible
39:03	just looks like fat but brown fat's particularly healthy because it it has a lot of mitochondria
39:08	and we think it also secretes little proteins that tell the rest of the body to be healthy in what way to be healthy
39:16	uh we're not sure yet we're not sure it's interesting oh man i want the answer to that question but it certainly
39:22	revs up your metabolism and will burn energy if you're looking to stay lean having a bit of brown fat is all good so
39:28	my my friend ray cronus and i have written on this and andrew bremer and at the nih we call it the metabolic winter
39:34	hypothesis and essentially it's saying that in our lifestyles these days we're always warm i'm wearing this jacket we
39:41	sleep with the covers on we turn up the heat we never get exposed to coal unless we we force ourselves to
39:47	and we think that that's possibly largely responsible if not you know maybe partly perhaps largely
39:53	responsible for the diabetic problem we have what okay so
39:59	if if you're cold at night you're going to burn a lot more energy staying warm yes turn on your brown fat
40:06	now that's going to keep people lean if we bundle up and and we eat the kind of diets that that uh we see in the
40:12	supermarket that's going to be doubly bad for our bodies yeah we're warm we're not losing energy and we're eating a lot
40:18	more yeah this is this stuff is so interesting okay so
40:24	what's your advisor i whatever you're about to tell me no i'm going to do it so like
40:31	how frequently do i want to be doing it is it every day what's that look like well what i do is because i'm busy and i
40:37	don't have a sauna or a cold tub at home i subject myself to this stuff
40:42	for about an hour on sundays and what i do is i spend about 15 minutes at 150 degrees
40:49	fahrenheit well that's reasonably intense but you get used to it uh then we go into the steam room
40:55	um you know we're sitting there chatting it's great uh temperature is lower in the steam room because humidity is is
41:02	saturated the roof's dripping on you hot water but that that i i don't know if the
41:07	steam helps but i certainly love the feeling of being in there and my skin starts to be healthier because of course
41:13	it's cleaning itself out and then the final thing i do is hot tub pretty hot hot water and then and then i
41:20	go and dunk below the water a couple of times in water that's less
41:26	than four degrees celsius so that that's so cold that it takes your breath away yeah yeah but it's
41:32	great interesting was there anything else on level three that we should know about yes
41:38	um so work that we've done recently uh just in the last year is finding ways to tweak the cells and the tissues of of
41:46	mice at least to reset the clock we've been working for 10 years as i said accelerating the clock we can drive
41:53	that hand of the clock forwards now we we cut the dna of the animal let it heal
41:59	and in doing so we distract those proteins from where they come from so we're
42:04	disturbing this survival circuit so much that we disrupt the spooling of the dna
42:09	and what we got was an old mouse by every account based on histology which is looking at the tissues based on their
42:16	physiology they got gray they got arthritis they got heart disease even and when we look at the molecular clock
42:23	that uh methylation clock they were 50 percent older communications they had more like clumps everywhere those methyl
42:30	groups were added to the dna right right okay so we had given them
42:36	heart disease and alzheimer's or dementia we'd given them all these diseases but by measuring the clock what
42:42	we had actually done is give them aging but that that was the first step that took 10 years the last year we've been
42:48	asking how do you get the hands to go backwards that's a lot harder but we were fortunate that
42:54	the 2012 nobel prize was one for the ability to reverse that clock in cells
43:00	it's called was the prize awarded to shinya yamanaka a japanese fellow
43:06	very smart guy and he found at least four genes that when you put into say skin cells of an adult if you
43:12	gave me your skin cells i could go back to laven basically clone you i could take your cells make a stem cell pool
43:18	and i could grow you into a new little liver or a new little kidney that's all easy not easy but it's doable it's
43:25	doable what that tells us is that those four yamanaka genes
43:31	can reset age if i can take someone who's in like you who's in their early 40s and make a new you as we've done now
43:37	for many species dogs cats sheep monkeys those animals we can reset the clock
43:44	hundred percent and those animals actually live a normal lifespan that tells us that the instructions to be
43:50	young are still in the cell somewhere as though there's a backup hard drive
43:55	that tells the epigenome those spools how to go back to be young again and get those methyl groups back to being young
44:01	again not up here but back there but don't strip them off too far to be a stem cell or i'll basically turn you
44:07	into the world's giant tumor yeah okay so one why do i become a tumor
44:13	because a tumor is a cell that doesn't know to stop so what is it that you're breaking in that process that that makes
44:19	it so um dysfunctional yeah so in terms of the clock let's just start with that
44:26	shiny yamanaka wound the clock so far back it went back to zero back to midnight that we do not want to do
44:32	because the cells lose their identity and that's the last thing we want to do we don't want to go back to us because it's dangerous to have a pluripotent
44:38	stem cell in the wrong place in the body of course it'll grow it won't stop growing but why doesn't why why does it
44:44	become a tumor why doesn't it become a liver or a lung like i would get the problem of having a liver develop in my
44:50	brain but i'm just saying like why does it become a tumor cell instead of an actual functioning liver
44:56	uh well so when you go back far enough and it loses its identity
45:01	it will just multiply into a mass without cellular identity so
45:06	there's something else going on that stops it from figuring itself out right so in the lab if we take a pluripotent stem cell and we want to make a liver
45:13	cell or a neuron a nerve cell we give it a bunch of chemical signals in what we call the
45:19	niche and when one of these cells lands in a niche around those old cells they'll use that stem
45:25	cell to rebuild tissue but imagine if we could reset the clock not all the way back to a stem cell but just partial
45:31	reset the clock so so that you could go back to being 20 again right that's what we're able to do
45:37	in some tissues in the mouse right now you do it on mass when it's cell by cell dna strand by dna
45:43	strand like how the hell do you get this to take effect through a whole joint let alone the
45:49	whole body yeah right now the way we do it is we inject a virus called an aav and this
45:57	virus will target certain tissues and deliver the genes to most of the cells in that tissue
46:03	for example we are treating aging of the eye in mice so we can take an old mouse
46:08	we deliver a virus the av into the eye tiny little prick
46:13	it's the same virus that that's used to correct genetic deficiencies in the eye right now fda approved drugs so this isn't science
46:20	fiction this is out there in in the world right now we give it give it to the old mice we give them an answer about it antibiotic
46:26	called doxycycline okay same thing you might take if you got lyme disease and that turns on these reprogramming
46:33	factors we don't use all four of the factors oskm they're called because one
46:38	of them causes cancer the m we leave off the m we put osnk
46:44	into the eye turn it on leave it for a few weeks measure what happens to the eye and
46:50	those mice can see again like they were young so we've tested three different types of
46:55	damaged damage to the eye the first one we did was a hail mary so the a lab near
47:00	ours across the road works on rejuvenating the spine and the optic nerve which is crazy yeah because we
47:07	know as soon as you're you know a couple of months old you're not going to regrow a spine it's one of the first parts of the body that ages in
47:14	fact but jellyfish can regrow axolotls can regrow an arm we lose that ability when
47:20	we're very very young so we the question was if we turn the clock back a lot
47:25	without osk genes will those nerve cells be young enough to regrow back to the brain if we damage them and that was the
47:32	experiment they pinched the back of the optic nerve so that the nerves were defective and they started to die back
47:37	towards the brain because the mice lost their vision we then turned on our reprogramming factors we now see that
47:43	the nerves get young again wind the clock back and they regrow back to the brain
47:49	we could give ourselves the healing ability that we only had when we were embryos and you start to think about what could
47:55	this lead to if we can do this safely of course safe is the important word across the body imagine one day you could have
48:02	every cell in your body able to be rejuvenated like that you cut yourself you break a bone you lose your your mind you have a
48:08	dementia you take a course of doxycycline for a few weeks and then stop switch it off again and you you
48:15	heal if you turn it on at high levels there's a lab in spain that has shown that you can get small tumors in some animals in
48:22	the kidney so we've been very careful to not just blast the cell with these
48:27	factors permanently we've titrated what we said brought the levels down to very low levels and
48:32	switch it off when we don't need it but we have given mice uh this virus throughout the body we
48:38	inject it into a vein and we turn it on we've left it on now expecting the mice to die
48:43	a year later they're perfectly fine wow so it appears to be safe but of course there's a lot more work to do i'm a
48:48	scientist and i'm developing drugs i have to be very aware of the dangers sure please nobody go out and try this
48:55	at home at all until we know more but the eye is a good testing zone because
49:00	it's it's protected and if there's a problem it's you know it's shielded from the rest of the body it won't go too far
49:06	but everything we know now is that it seems to be very safe at least in the eye wow this is crazy so that is
49:13	is there an element of getting better improvement human performance or anything that
49:18	you can tease us with well we've actually published results
49:23	that in mice if you give them an nad booster molecule that will turn on these pac-man enzymes called the
49:30	sirtuins those mice when they're old can now run fifty percent further in fact some of
49:35	our old mice ran so far that the treadmill stopped because mice are not supposed to run more than three
49:40	kilometers we haven't talked about nad yet tell me what nad is what are the precursors how do i supplement for it
49:48	uh so there are a few on the market i don't endorse or sell anything just by
49:53	the way even if you see me on line that's not me so that said there are there's one
49:59	called nr which is stan which stands for nicotinamide riboside which is a very early precursor to
50:05	making nad in the body there's an intermediate from that called nmn not to be confused with m m's please
50:12	don't do that that's not healthy um and then the cell turns nmn into nad
50:18	and you can take all three actually and or each one of those three and raise nad levels in
50:24	animals and now we're doing myself and many others are doing human studies and we've seen that
50:30	nr and in my case nmn does raise the energy levels of older people and and
50:36	young people alike up to levels that we think you could rarely achieve even with uh being a marathon runner that's crazy
50:43	so just to bring this home for people talk to me about your dad and his uh n
50:48	of one experimentation with nmn yeah so my father has been on the same
50:53	regiment as me resveratrol for over a decade the red wine molecule
50:58	he's been on metformin longer than me because he had he was a borderline diabetic type 2 diabetic
51:04	and he's also on anime now and he seems to be doing great he's now 80. when he was in his 70s he was he was
51:10	slowing down his he was starting to say the same things twice you know typical 70 year old
51:16	um he's doing great now he's 80 he's got a new lease on life he started a new career down in sydney he's hiking at the
51:23	world right now he's traveling around america driving his elderly friend around his friend unfortunately ended up
51:30	going to the hospital the last few days so my father is taking care of his friends who he's seeing on the decline and he's if anything
51:37	improving every year i'd love to hear more about resveratrol which is something that i've completely
51:42	written off until i started researching you um it seemed for a red hot minute like it was real and then it seemed to
51:48	completely die and i know that you got sort of caught in the middle of some of this stuff
51:53	so where has all the forget like what pop culture thinks of it like what's the
52:00	reality of it yeah so resveratrol was a proof of concept molecule back in 2003 the first of its kind that could mimic
52:06	caloric restriction make mice healthy on a high fat western diet and it was it was a great proof of
52:12	something that we were trying to figure out and it led to drugs that went into humans that looked really promising
52:19	i got embroiled in a scientific and a a corporate war song in the case of pfizer they put out
52:25	a scientific paper that said essentially everything that david has said is wrong okay and then that was a great headline
52:33	harvard scientists started companies is wrong okay and you know and then i spent about a week in bed saying [ __ ]
52:40	the world you know why am i doing this why am i working so hard for society if they don't care but i worked my way out of
52:46	bed i thought let's dig deep and see if they're right or if we're right and so for another three years we really
52:53	worked hard in my lab at harvard to test whether we were right so the question was with this pac-man that spools the dna
53:00	does resveratrol work on it or is it working on something else and that to scientists is really
53:06	important because if it's not working on this all the drugs that we're trying to work on this are probably working
53:12	um the wrong way that we thought to cut a long story short what we found and published in the journal science
53:19	which is one of the top you can do and i say that because it's validated science
53:25	is that we show that resveratrol does bind to the pac-man and it is responsible for this and we now have new
53:31	information that we haven't published but i'll tell your audience about it we've made a mouse that is resistant to
53:38	activation of the pac-man we can tweak the enzyme just in one amino acid in that protein out of about
53:44	a thousand that blocks this movement activation it's normally chewing like this
53:50	but if we add resveratrol to a normal mouse it'll do that to our mutant mouse it's this and which is better
53:57	the rapid munching rapid munching's better okay because the rapid was we think was responsible for the health benefits and the longevity so what
54:03	you're showing is by slowing it down you cause real problems and thusly if you have resveratrol on there and get it
54:09	munching really fast that you've done something positive right and our mutant mouse should be resistant to the
54:14	benefits of resveratrol if we're right but if pfizer is right then resveratrol
54:19	should still provide benefits even though this enzyme because it's working on some other some other way got it so the mouse that could not be sped up the
54:26	mutant mouse does not live longer when given resveratrol on its high fat diet interesting so that will be the
54:32	punctuation mark the fu we were right but but interestingly the world has
54:39	moved on right well i'm i'm left to clean up the pieces right yeah so and when you say the world has
54:44	moved on you're talking about people like me who just assumed that it was garbage and that it's not real and right
54:50	okay so um you've said that the only supplement you take is vitamin d um so
54:55	how are you getting resveratrol in the system is it a drug do you have to have it prescribed
55:00	uh well i'm taking resveratrol i have um and would we call that a supplement sure and it's commercially available
55:07	uh it is if it's a legitimate seller and it's 98 plus percent pure it it seems to
55:12	be similar to what i take and ballpark how much do you take
55:18	um i take a teaspoon into my yogurt that's probably close to a gram every day every day yeah okay
55:24	uh resveratrol roughly a gram are you taking nmm or is nmn or is that
55:29	just your dad uh both of us okay and then um metformin right those three anything else those
55:37	are the main things that i think are helpful and i've been monitoring my blood by chemistry so
55:42	i and you said you took an mri of your heart right which i love what are things that we should be
55:48	testing assume for a second i'm willing to go all the way do any crazy test to know if what i'm doing is working um
55:54	what would you recommend well i avoid x-rays and ct scans unless
55:59	i have to sure right if your doctor says go for it please don't refuse that but otherwise don't do
56:05	it for fun don't do it because you're curious because those ct scans will break your dna and when we we break the mouse's dna
56:12	it's a its age goes up by 50 percent so whoa right so avoid dna breaks as much
56:18	as possible um what i do is i take a blood test from a company called inside tracker which in
56:23	full disclosure i invested in years ago and they look at about 30 parameters in
56:28	your blood and give you feedback it's doctor supervised so it's it's legit and it's based on a lot of science
56:35	and that at least gives you some feedback about your body about what's actually happening if you change your lifestyle
56:40	or you take a supplement or even a new drug for that matter so you've got to have you've got to be monitoring because
56:46	you don't you don't want to fly blind you don't know if for you you're doing harm or doing good um so do do a blood test at least go to
56:52	your doctor and have a blood test for for a good goodness sake you could have your genome sequenced or
56:59	do something that looks at the the variance in your genome for relatively little cost i think it's 99 now
57:06	i gave a test of that kind to my whole family as christmas present and what we've learned is that some of
57:12	our members lab members are not lab members family members have variants that predict longevity some don't some
57:19	have mutations in their genome that are a little bit scary down the line you could get your dna
57:25	methylation age determined the true what's called the horvath clock some people measure their telomere
57:31	lengths um did you have a biopsy to do that or can you do it from blood blood blood test is
57:36	fine what is up my friend tom bill you here and i have a big question to ask you how would you rate your level of
57:42	personal discipline on a scale of one to ten if your answer is anything less than a ten i've got something cool for you
57:47	and let me tell you right now discipline by its very nature means compelling yourself to do difficult things that are
57:53	stressful boring which is what kills most people or possibly scary or even painful now
57:58	here is the thing achieving huge goals and stretching to reach your potential requires you to do those challenging
58:05	stressful things and to stick with them even when it gets boring and it will get boring building your levels of personal
58:11	discipline is not easy but let me tell you it pays off in fact i will tell you you're never going to achieve anything
58:16	meaningful unless you develop discipline right i've just released a class from impact theory university called how to
58:22	build ironclad discipline that teaches you the process of building yourself up in this area so that you can push
58:27	yourself to do the hard things that greatness is going to require of you right click the link on the screen
58:33	register for this class right now and let's get to work i will see you inside this workshop from impact theory
58:38	university until then my friends be legendary peace out

This Causes Aging

58:43	for a long time i was really focused on living forever and that was the dominant thing i thought about as i mapped out my
58:49	life and then about a year or two ago it started to feel more important to recognize my mortality and part of it
58:56	was i i had really lost faith that it was going to happen in my lifetime and
59:01	i definitely want it to happen in researching you for this episode i am regaining belief that it we really may
59:07	hit health escape velocity in my life and so in the first half of the show i want to talk about um why we age exactly
59:15	and you've gotten extraordinarily good at mapping that out with real conviction and then in the second half we'll talk
59:20	about what we can do on an individual level to really slow that down or possibly even reverse it so i want
59:26	people to stick with me because i'm actually going to start with a story and a quote and
59:32	i want to make sure that people know the map of where we're going so first the story on christmas eve
59:39	i was throwing a little party for my family and it was a poker party we had a dealer
59:46	come he was 40 years old and the energy's high imagine balloons
59:51	everywhere it was actually a birthday party happens to be somebody's born in my family on new christmas eve
59:58	and i go into the kitchen to get a drink and my wife runs in and says we think the dealer's having a heart attack
1:00:04	she's like you need to get in there right now and so i rush in to the room where this is all set up and he's just
1:00:11	sitting there holding his head like this and i said i don't think he's having a heart attack i think he's having a stroke
1:00:16	and you know long story short he ends up not surviving oh no and so
1:00:22	he was in a um coma for i guess five days and and they end up taking him off
1:00:28	life support life support and he passes away and i was like this guy is 40. and so
1:00:34	the question really becomes how do we get good at understanding where we're at
1:00:40	biologically what is our real age not our as you say not the number of times
1:00:45	that the earth has gone around the sun but how old are we really from uh
1:00:51	uh the things that we can measure and are they giving us real information so that's the story now the quote this is
1:00:57	you in your own podcast this is a quote pulled from your first episode in my lab now we can control aging very
1:01:04	precisely at will we can speed it up as fast as we want in an animal and even
1:01:09	reverse it so aging is now controllable we have the technology to control how
1:01:15	fast we age we can measure that slow it down and even reverse it it's going to
1:01:21	fundamentally change the course of human history i have the [ __ ] chills man
1:01:26	so that's a big statement it's a bold statement and what i want to do now is
1:01:34	walk through what do we know how do we measure it and then we'll later get to what we do about it but i'm
1:01:41	a big believer if you understand the mechanisms you can make change what are the mechanisms why for real why
1:01:48	do we age yeah yeah so when i wrote my book lifespan um
1:01:55	it was a theory um about why we age and when i boiled it down
1:02:00	to its essence i realized and i theorized that aging was a loss of information
1:02:08	so in our body we have two types of information when we're born or even when we're conceived there's the one that we
1:02:13	all know about we can get our dna red that's the genome but there's this other layer called the
1:02:20	epigenome and why is that important because if you just have dna and there's six feet of it
1:02:25	in every cell it's just a chemical it's not going to give you life what gives you life
1:02:31	is the the system that reads the dna the right way but we've got this chemical that's
1:02:37	like a hard disk driver or flash memory that has these letters atcg that's it period they're just four
1:02:44	four chemicals that get strung in different order and the cell can write those down can
1:02:49	build those chains and that's how we copy the dna i don't i i run the risk of
1:02:54	taking us off track here but i'm very curious how where does it get the letters
1:03:00	the the enzyme or the protein enzyme proteins synonyms yeah okay so where does the
1:03:07	protein go great is there a bucket of letters like i had as a kid that it like reaches into and grabs one of the
1:03:13	letters out there are yeah they're floating around and then there's literally atcgs
1:03:20	they are we're filled with the building blocks of dna and proteins one are the dna bases
1:03:26	atcg they float around and because they're just floating around they're buzzing around and so an enzyme
1:03:33	sees probably 10 000 molecules in a second it's really quick and it picks the ones
1:03:39	it wants so okay i want an a and it's it's basing it's looking at the dna and it says you need a c right now and it
1:03:45	reaches out grabs a c you need a g now it grabs the g that's literally what's happening yes that is insane i cannot
1:03:52	believe i've never asked that question that you're freaking me out all right keep going and how does it know whether it's a g or a c to put down
1:03:58	because it's copying the dna you've got one strand that has the actg
1:04:03	and that protein will look for what matches the g and a g always matches a c
1:04:10	and an a always matches a t so there are pairs of dna that make the rungs in that ladder of that spiral that
1:04:17	double helix but you generally you actually need a template
1:04:22	that's why you have double strands one of them is a template the other one you then match to that
1:04:27	in the other direction so it's not like my fly here which is a zipper that goes up it's a zipper that does
1:04:33	that as it's being built interesting uh but we we get that from our parents right without any dna there's nothing to
1:04:40	copy getting back to the memory there's something i think you'd like to hear because you're very much into
1:04:47	digital and nft world it turns out that the best way to store memory now is
1:04:54	biologically in a little test tube we can store all of human information
1:04:59	and we we're built what we but humanity is building the machines to write down
1:05:04	those letters and store all the world's information in order and then the readers to get that
1:05:10	information back out so why is that important because computers don't last for a thousand years and you can't fit
1:05:16	all the world's data in a test tube but technology is pretty much there to be able to do that
1:05:22	whoa okay so that's insane going back to the reader the reader is
1:05:29	that little um protein enzyme that's grabbing the
1:05:35	the matching pairs and building it up and so all day long it's just like here's a half and i need
1:05:41	to match that half is that the idea yeah well there are two things you can do with dna you can copy
1:05:47	the dna so that the cell has extra chromosomes that then divide and you have new cells
1:05:52	that's copying the genetic material but then you can also use the gene um so it's a string of a few thousand of those
1:05:58	letters to make more protein and so instead of make copying it making
1:06:03	dna this is where rna comes in so we've heard about rna based vaccines mrna
1:06:10	is one type the cell makes the mrna it's called messenger rna because it's a messenger
1:06:16	and now that message which might be a thousand of these letters floats away from the chromosome and another machine
1:06:23	grabs that and now has its own template to grab not dna bases not the atcg but
1:06:29	amino acids 20 of them so it's programmed to look for these
1:06:34	um sentences basically so rather than an individual letter i'm here for a whole sentence or a maybe even a chapter it
1:06:41	tells me to do something and is that something to create a new protein is that what all of
1:06:47	these do mostly okay mostly you can you can make rnas and you can make uh protein but and
1:06:53	dna but mostly we're pretty much made of protein those proteins are either structural from
1:07:00	muscle or they carry out chemical reactions making new dna making proteins making lipids making energy without
1:07:07	making energy both of us would be dead in less than 30 seconds we need to always be making it
1:07:13	it's quite uh we're always thirty seconds away from death as you mentioned life is tenuous when you get down to
1:07:19	that level um and so what what happens with aging is that the ability of the cell to know
1:07:26	which genes to read goes awry those proteins that would normally turn
1:07:31	on a gene that makes a brain cell know to be a brain cell get lost those proteins instead of
1:07:37	reading the brain cell gene will go off and get distracted and start reading a liver gene or a skin cell gene
1:07:42	okay so now here's where i think we have to get away from metaphor distracted and now get into and i know your theory
1:07:49	quite well because i've gone through it so many times but there's a part of it that i don't understand well and that's the sirtuins
1:07:56	so since we haven't said that word yet today
1:08:01	talk to me or explain what is the when the the reading of the information
1:08:07	begins to go wrong what happens that causes that to go wrong because it's not like the
1:08:14	the protein gets bored and starts watching baseball right so it's not distracted in that way but there
1:08:19	actually is something going on that we can actually see and understand what is that thing
1:08:26	well so the sirtuins we have seven of these genes that make seven different proteins in our cells each one
1:08:33	uh they're very ancient so the sirtuin actually controls which genes are on and off okay so the spooling of the dna yeah
1:08:41	so so that six feet of dna is not just flailing around in liquid that would not be life what
1:08:47	the cell does from conception and before that tell people why that wouldn't be life you threw that off but that's
1:08:53	actually really fascinating so if the dna is just a fully naked strand that can be read in its entirety you don't
1:09:00	have life that isn't self-evidently clear why wouldn't that be life
1:09:07	well you need to organize it very well because we're multicellular a bacterium
1:09:12	doesn't need to worry about it because it's just one cell it knows what it needs to do and its offspring are very similar
1:09:19	our bodies are made of a trillion cells and each one
1:09:24	literally is different right even if you measure an adjacent cell it's behaving slightly differently
1:09:30	but if you take a brain cell a nerve cell compared to a liver cell it's totally different but remember they have that same six feet of dna
1:09:37	so what we need to do as multi-solar organisms to survive is to get rid of not rid of but but hide
1:09:44	and compact and silence parts of our dna that are not useful for
1:09:50	that cell type so the reader isn't told your job is to read and recreate liver
1:09:55	cells it's told read whatever is exposed and there's some other mechanism this is
1:10:01	your job is to hide everything that isn't a liver cell and that's a sirtuin
1:10:07	the sertune is the one that hides everything yeah and sir stands for silent information regulator
1:10:13	and that was the clue to this whole information theory of aging it was right there in the name
1:10:18	and what we find is that those spools so if you zoom let's zoom up on the genome now you'll see that most of it is
1:10:24	compacted because most of the genome is is not used we use a few percent of it the genome is
1:10:30	another word for your strand of dna correct yes so most of it is bundled up in these little packages and when we say
1:10:36	it's bundled up is it put in something or is it just squished together in a way that's impossible to read
1:10:42	it's really precisely packaged there are four proteins called histones okay and they
1:10:47	make a circular little ball and they love dna so what happens is the
1:10:54	dna wraps around those histones so you get two wraps around one histone and it's wrapped around by a certain
1:11:01	in part in part but there are there are enzymes that do this as well more machines that grab
1:11:07	dna and wrap it around twice grab another histone stick it next to it and
1:11:12	wrap it around more so it's like spooling you're wrapping string around a ball and then you get
1:11:18	these balls on a string it's called and that for the technically minded is called chromatin and if you take those
1:11:25	balls on a string and then wrap those up into bigger bundles eventually you get what we call a
1:11:31	chromosome which you can see with your eye or at least with a pretty weak microscope
1:11:36	this is incredible we start bundling it we have the sirtuins their job is to silence the vast
1:11:44	majority of the information on the dna and then we have this other enzyme that
1:11:50	comes in and it its job is to read what is exposed so the information theory is
1:11:56	you've got the whole all the possible things hey you're an eye cell you're an eyebrow you're a
1:12:03	heart cell you're a brain cell you're an amygdala brain cells so it's like all of
1:12:08	these incredibly specific instructions [Music] and they're all linked together and so
1:12:14	what we have to do is come up with some very intricate clean way of
1:12:21	making sure that the right information is read at the right time and the solution that nature has given us is
1:12:28	this wrapping of the bundling of dna i think is the word that most people use to make it impossible to read everything
1:12:33	but certain sections but what parts of the bundle are exposed are epigenetics
1:12:39	at work which are based on environmental cues that we give our body well kind of epigenetics refers to all
1:12:46	those machines that bundle up the dna and read the dna that's the epigenetic system
1:12:51	it's like um in a computer the code would would be one thing and then all the machinery to
1:12:57	read that code which is the computer um is the epigen epigenome so which is
1:13:02	kind of complex you can't say oh that's an epigenome protein there are hundreds but certains are major players
1:13:09	and they from birth say that this gene needs to stay off because it's a liver gene that's working
1:13:15	shouldn't work in the brain so don't expose it don't expose it so we've got bundles bundles bundles a big loop
1:13:21	bundles bundles bundles and some of these loops are really important for when we're developing as an embryo
1:13:27	one of these big loops it's called hox and there are 13 hox genes hox and they get red in a certain order the
1:13:34	first ones get red and tell the the little embryo this is your tail uh which eventually goes away in humans
1:13:40	but we have a tail and then others your midsection then this is your your upper body then your neck and your head that's
1:13:46	what this hox does and and eventually once you're born it gets bundled away okay we don't need
1:13:52	those anymore we've built the body it's got a head and a tail hox is there but when we were looking at
1:13:57	older cells in mice and in humans guess what that bundle of hox developmental genes
1:14:03	started to open up again because the sort of got moved away and did some other things
1:14:09	during aging and now we've got genes that tell us head to tail coming on in our body when they shouldn't and
1:14:16	that's part of the problem with aging which is genes getting turned on when they should be kept off for decades
1:14:24	and then cells start to get confused does the revealing of the wrong things that unbundling
1:14:29	[Music] does it happen because the sirtuins are not rebundling them or are they actively
1:14:37	going in and unbundling things that they shouldn't well what we think is happening is that they physically
1:14:43	move away to other parts of the dna molecule where they shouldn't normally be that's the distraction
1:14:50	they get called away to do other things they are very good at handling emergencies these are emergency survival
1:14:57	proteins that they have two roles one is to make sure that everything's good every day
1:15:02	super optimal health stay young but they also through i think evolution
1:15:08	and very early in evolution their role was to put out the fire uh and so they go away they actually
1:15:14	leave where they should so that they're bundling and for a few minutes until the emergency is fixed
1:15:21	they actually float away go repair something so it might be a broken chromosome somewhere else
1:15:27	over on another chromosome they go there they fix it and then somehow they find their way
1:15:33	back to make sure that bundle is you know maintained but if you keep doing that
1:15:39	and we every cell gets at least one broken chromosome every day and that's that's trillions in in our
1:15:45	body every day these fractures get i call it distracted but basically they're doing this other role putting out the
1:15:51	fire and then coming back if you do that for decades eventually
1:15:56	some of them they're lost they don't find their way back and these loops that shouldn't of dna that should never be
1:16:02	turned on start to come on i may have been wrong then maybe distracted isn't a metaphor it's they
1:16:09	literally have so much work to do which would make sense and so now to actually use a metaphor you talk about for people
1:16:15	that know what a cd is uh that you would get these scratches in your cds and it would cause the songs to
1:16:21	not play right it was really obnoxious actually and
1:16:27	that idea of aging you're going to get these scratches
1:16:32	you're going to get the the fires that have to be put out the certum is going to get busy dealing with brakes and
1:16:39	whatever and so it's got to go handle that put out that fire deal with that break
1:16:44	um and as we age there's an accumulation of
1:16:49	damage that we do and so these things are constantly busy and therein lies
1:16:55	the information theory of aging that the sirtuins are too busy to maintain the
1:17:01	integrity of the bundling of the dna in a given region which will be different everywhere
1:17:07	but it's no longer holding to the integrity of just be a brain cell just be a liver cell just be a pancreas cell
1:17:14	and the readers are only instructed to read what's exposed and so now if your brain
1:17:21	cell also has a little bit sticking up for skin cell or tail or whatever
1:17:27	now all of a sudden you have a dysfunctional cell in your brain that's aging as i see it that cells lose
1:17:34	their identity we call it x differentiation which is an old theory but this is what we've given a name to
1:17:40	it and so cells when you're developing from an egg fertilized egg to a baby to an adult that's called
1:17:47	differentiation okay cells get their identity the bundles and loops get established that's youth that's health
1:17:55	x differentiation is what happens after that but then the question is with the scratches on the cd
1:18:02	can you get rid of them can you polish them can you get those bundles that have been exposed to go back
1:18:07	to where they came from and reset the age of a cell and get the brain to wake up and
1:18:12	remember oh crap oh yeah i forgot i am actually a brain cell or an eye cell
1:18:18	so this was the big question that i had after figuring that other stuff out we just talked about was is there a backup copy of a youthful
1:18:27	epi genome what does that mean does the cell know that that loop that's come out
1:18:32	that it needs to go back in for that to be the first time well we inherited that from
1:18:39	our parents that pattern does it memorize that like okay if i'm a certain
1:18:45	am i only floating around a given area so i know hey this is how it's supposed
1:18:51	to look so we get some signal that it's like okay we're done growing head tail
1:18:56	bundle those back and now this is what it should look like forever and
1:19:03	how would it know that well what it what the cell does in part is it puts chemical tags
1:19:10	on regions that need to be bundled up known as methylation that's dna methylation right and you can also put methyls these
1:19:18	little chemicals hydrogens uh on a carbon you can also put them on those bundling proteins called histones
1:19:24	which we talked about beads on a string can be modified but the most important one for long-term maintenance
1:19:29	of the epigenome is this dna methylation uh once you put a dna methyl carbon
1:19:36	hydrogen hydrogen on a dna molecule which goes on the letter c not all four but mostly it's on the c a
1:19:42	little bit on an a then that tags that gene for a certain behavior
1:19:48	mostly it means shut that gene down and leave it alone but over time possibly due to sotuns moving away
1:19:55	perhaps other things that dna methylation pattern across the genome there are
1:20:00	millions of these little tags starts to go away they're dissolved or
1:20:05	broken down somehow well there are enzymes called dna d-methyl lasers
1:20:11	that take them off and they they start to do that job when they shouldn't why would we do that job
1:20:18	ever what's the use case for that there must be one uh yeah well cells that come from stem
1:20:23	cells need to grow into different cell types we have stem cells that grow skin stem
1:20:30	cells that grow at all times yeah we need those if we get damaged we need to rebuild if you if i cut part of your
1:20:36	liver out it'll regrow into a new liver because you've got stem cells our gut is always replacing itself
1:20:41	because it's it's hitting all sorts of things down there so they're little stem cells but for those stem cells to rebuild five or ten
1:20:49	different other cell types you need to be able to alter that pattern of dna methylation
1:20:54	even when you're an adult but that system goes wrong in a way that
1:20:59	doesn't make us healthier it does the opposite it makes cells more stupid cells forget
1:21:04	what type of cell they should be and that's x differentiation but now the question is can you redifferentiate can you get them to go
1:21:11	back to the way they're simple stem cells if stem cells are the ones that carry
1:21:17	that like pluripotency of like we could become anything because it sounds like i mean
1:21:22	to your point about the liver cell there are already some that are doing this that know no
1:21:27	the liver is gone i know what i need to do though to rebuild it yeah and so
1:21:34	is that just that that mechanism is limited to the liver and the intestines and therefore it's not doing that job
1:21:40	elsewhere or well we could we could have reversed aging just by making all cells
1:21:47	a stem cell we have the technology to do that that was the 2016 nobel prize
1:21:52	yamanaka professor yamanaka discovered that there are four genes that if you put into adult cells will erase
1:22:00	all their identity all those loops and bundles will just get erased those methyls will get erased and you have a
1:22:06	primordial pluripotent stem cell and any high school student can do that these
1:22:11	days just put four genes internally insane okay but you don't want to do that because you would become the world's
1:22:17	biggest tumor that doesn't sound fun yeah that's not age reversal that's instant death
1:22:22	and if you do that in a mouse i i we haven't done much of this but there are labs that do this uh the mice die within a couple of days
1:22:31	they just get riddled with tumors well over time if you do it a little bit they get tumors but if you turn it up a lot
1:22:38	then the cells just forget what to do and the mouse dies even without tumors the cells just need
1:22:44	to know how to work so you don't want to do the yamanaka treatment in a living thing other than a
1:22:50	cell in the dish but we did stand on the shoulders of professor yamanako because
1:22:55	we thought what if we could find a combination of those genes that doesn't take you all the way back
1:23:01	to zero to be a stem cell but it could take you back to an earlier state
1:23:06	that would never go back to being a stem cell because we don't want to get cancer while we're getting younger
1:23:13	and so it'd be like polishing the scratches on your cd but make sure you don't do it too much
1:23:19	because you'll erase everything you've got to maintain some surface and it was a few years of work and i had
1:23:25	a student in the lab a brilliant hard-working guy yuan cheng
1:23:30	liu and yuan cheng was pretty frustrated he kept putting genes into these old cells
1:23:36	in the dish and they would turn cancerous or they would die that was one or two
1:23:42	outcomes of this this binary so they would either replicate uncontrollably yep without remembering when to shut off
1:23:49	or they just have to give up i'm out of here this is too crazy uh but we hit upon a magical combination
1:23:56	and he was literally about to quit his phd he said i can't do this anymore whoa i gotta change topics i'm i'm out of
1:24:02	here because it's never going to work david you're insane you can't partially reverse aging it's not going to work
1:24:10	and he had every reason to believe that i mean how crazy is it the the cell would remember okay this gene here needs to go
1:24:17	back to that state and this gene over here needs to do that how could there be a memory in the cell
1:24:23	of youth and we didn't nobody knew until we did the experiment and the experiment that i said he should
1:24:29	do before he quits was to don't use all four of these yamanaka genes
1:24:34	and and in fact one of them causes cancer we know that so it didn't take too much of a genius to say look just leave out that gene
1:24:41	it's called c mick and see if the other three would work and no one knew if three was sufficient
1:24:47	most people thought it wasn't and he put those three genes in and they're called o for oct4 sox2 s and klf4 osk
1:24:56	and if you're wondering what do these genes actually do they make proteins that turn genes on and off during development right starting to see the
1:25:03	theme here and they work with sirtuins and those dna methods all right so you
1:25:08	put in those three genes into old human cells in the dish and they they looked fine they kept
1:25:14	growing they didn't turn into a tumor they didn't grow uncontrollably and they didn't die and then when he measured the patterns
1:25:22	of which genes were on and off they resembled a young cell again
1:25:28	and that was a eureka moment in the lab i would say we could reverse aging in the skin in a dish
1:25:35	but the real experiment that changed everything was he then made a virus a domesticated
1:25:41	virus we call it an aav and he could now deliver those genes into a living organism
1:25:47	which in our case is typically an old mouse and he did a very clever thing he said i
1:25:52	want to work on the eye his father had a biotech company that that is trying to
1:25:57	solve um blindness cue blindness and i said the eye you're kidding me i know nothing about the eye
1:26:03	blindness has never been cured uh you know how's it gonna be possible to deliver
1:26:09	this into an eye let's just do the liver i understand the liver it's it's easy we'll just get it
1:26:14	in he said no trust me i've got the good feeling about the eye right all right fine and i've learned over the years if
1:26:19	somebody really wants to do something let them go do it and usually they're right there's this thing in science where you
1:26:25	have this gut feeling but you're not really sure where it's coming from so there's a spirituality yeah
1:26:31	and i've learned to tap into that as do students it's one of the things i teach them
1:26:37	so he took an old mouse actually the first experiment was he actually caused the mouse to become blind
1:26:44	and then he put the virus into the eye just straight in turned on his three
1:26:49	yamanaka genes osnk uh and then he looked four weeks later
1:26:56	at what happened in that eye and he found out that the optic nerve that was damaged
1:27:02	started and for the most part grew back and that never happens optic nerves don't grow back if you go blind from
1:27:09	damaging your eye you're not going to see again same with your spinal cord same with your brain damage the central nervous
1:27:15	system with nerves in your body does not grow back it's a fact of biology and here was one
1:27:21	change showing he was able to do that so why is that relevant to aging because when you're
1:27:26	very young if you damage your optic nerve or even your spine or your brain it can
1:27:32	grow back but we lose that ability as we get older and he was juan cheng taking the eye back so young
1:27:38	that it could regenerate and function but then he did something very clever he then put it into a mouse that we gave
1:27:45	glaucoma to so pressure in the eye damages vision and then he also did it to old mice that
1:27:50	had just aged and were blind as well and he started to cure blindness with
1:27:56	his treatment and we could now measure the age of those nerve cells and they were
1:28:01	literally younger and those those bundles and those loops we can measure those and the dna methylation the
1:28:06	chemicals we can measure those and he was sending them back 75-80 percent of their age but not to
1:28:13	zero or not 100 so he sent me that i i don't know if
1:28:19	i've still got it on my phone but it's recorded in my book because uh he sent me this text that said
1:28:26	david i've got to show you these photos and he sent me an image of the nerve which is a long strand it's orange we stained it orange
1:28:33	so you can see it and the damaged one just looked like there were a few dead cells but the one
1:28:39	that was reprogrammed was bright orange all the cells almost all had survived the damage and then
1:28:44	they started to grow back towards the brain from the eye of the brain and you could see it's like a jellyfish tail and
1:28:49	he sent me pictures of that and he said i thought i was going to fail but do you see what i'm seeing and i
1:28:56	said yeah i see it what are you seeing i said the future wow and that lit is literally what we saw so
1:29:04	now we know you can reprogram other tissues it doesn't have to be the optic nerve it can be the retina it can
1:29:10	be the cone cells of the eye and so we're reversing aging of the eye that's not
1:29:16	hard at all but we can reverse the age of the liver the skin other labs are doing the spleen
1:29:23	thymus through this method so it's it seems to be a somewhat if not
1:29:29	universal method of resetting the age of the body safely safely is the key
1:29:36	and because i started a biotech company called life biosciences that wants to cure blindness and other age-related
1:29:42	diseases using this method for the last two and a half years we've been doing safety studies
1:29:47	in mice and now we're in non-human primates and those animals are fine we can blast these three genes
1:29:54	in the animal and they're fine they don't get tumors their eyes are healthy
1:29:59	you don't get uh malformation of the eye so it's great we lucked out humanity lucked out that we can actually do this
1:30:05	and that there's a backup copy of youth in each of our cells that can be tapped into
1:30:11	that's crazy do we know what is going on that allows it to realize what it's
1:30:17	supposed to look like what the bundling of that cell is supposed to look like because that is what's going on right it
1:30:23	suddenly remembers up these are sticking out they shouldn't right and how do we go from it has so many fires to put out
1:30:29	that it's just roaming all over the place and it can't get back how do we sort of give it that breather to come
1:30:34	back and go not only do i remember how to bundle this but i've got the time to dedicate
1:30:39	to bundling it correctly again well the bundling it takes a few days um
1:30:44	and a week you're getting pretty close a month you've now got vision back
1:30:50	um and then actually by the way if you stop the treatment we now i didn't know this when we talked last but when you stop the treatment it's long
1:30:56	lasting that mouse will still have young eyes six months later and i always not i still do i want to
1:31:03	test how many times can you reset uh because if it's if it's once it's interesting if it's 100 times it's super
1:31:09	interesting no joke and we we couldn't do that experiment because the mice were dying from old age
1:31:15	with super young eyes so we got to reset once but now we're resetting entire mice
1:31:22	and by the way you mentioned earlier the quote from my podcast we can actually control aging in the other direction we
1:31:28	now know how to distract and move the sortuans away we cut chromosomes and let them move away
1:31:35	and those gene packages open up the same as aging so we can make a mouse
1:31:40	poor things that we can make them age rapidly so if you were to come to my lab i could show you a mouse that's a twin
1:31:47	and it's brother let's say brother and sister the brother will be 50 older than his sister but they were born on the
1:31:52	same day whoa and now we're reversing the age of those mice
1:31:59	our main mouse is called lisa by coincidence and we're taking lisa and we're going to rejuvenate her uh so that
1:32:05	she hopefully gets back to being so better up and now you want to see if you can take her back jesus man like this is
1:32:13	i mean you said that this is going to be remembered as the moment that human history changed i mean but that's crazy
1:32:19	if this ends up working out like this is really bananas so aging actually has been worked on for

How to Understand Aging

1:32:26	about 5 000 years or more and just in the last 20 years we've come up with a set of hallmarks of aging there
1:32:33	are about eight of them and i think many of your viewers will know that there's telomere attrition the ends of
1:32:38	chromosomes get shorter mitochondria the power packs we run out of energy as we get older there's a list a long laundry
1:32:44	list and most of the people in in my field have said okay we've we've figured out aging we've got this list we put in
1:32:50	a nice pie chart and that's it but what i'm saying is that why does all that stuff happen it's not
1:32:57	enough just to tick off what happens you have to understand is there an upstream cause of all of that
1:33:03	and so in in my book and in scientific papers we are now putting out for the scientific community to read as well
1:33:09	what we think is going on is that our bodies are losing essential information as we get older that drives
1:33:16	many if not all of those hallmarks that we know exist so what in what way is the epigenome
1:33:24	involved in this how are we losing the information give people a quick little diatribe about the difference between
1:33:29	genetics which i think they get and then the epigenome and epigenetics and and how that plays out yeah yeah for sure
1:33:36	it's not that complicated there's really just two main types of information in our body that we get from our parents
1:33:42	the first is genetic we all know about dna and the four letters atcg uh it's a
1:33:47	long molecule in cell and it's a string of letters that's digital that's like the music that's on on a dvd those
1:33:53	things we used to use uh to store movies but there's another level of information that's above that in cells which is the
1:34:00	reader of the information that's called the epigenome and that really is different because
1:34:06	it's analog information in the same way that records and cassette tapes
1:34:12	they sucked they were terrible at storing information but the problem is we have an analog version of information
1:34:19	the epigenome which controls which genes in the string of dna are turned on and
1:34:24	off and that's why are you considering that analog i don't think i understand how it actually works like i can imagine
1:34:30	dna sequences as just sort of repeating the atcg
1:34:36	code but what is analog about the epigenome this reading about it in your book is the
1:34:42	first time that i began to imagine it in a different way
1:34:47	well it's very clear that that if you just have four letters that's digital so we understand that but the epigenome
1:34:52	is the structure of how the dna is organized so dna isn't just flailing
1:34:58	around like a string it's actually packaged up around proteins we call histones and it's like if you spool your
1:35:04	hose in the garden you loop it around and then you can put those loops into bigger structures then you get a chromosome which you can see any high
1:35:09	school student can see under a microscope that's that chromatin structure as we call it is the epigenome
1:35:16	and so when when the hose is looped tightly and spooled up that's stopping
1:35:21	genes from being red so genes are off when they're compacted but also if the cell needs to read certain genes and a
1:35:27	nerve cell needs to read the nerve cell genes and the liver cell needs to read specifically the liver cell genes and so
1:35:32	they open those ones up and now the cell can get access and read those that's an analog system because it it's varying
1:35:38	all the time it changes when you wake up what you eat so it is literally the amount that the um
1:35:45	the dna is unspooled and the place in which it is unspooled so that it can be read
1:35:52	right and that's what determines the cell's function and identity which we you know when we're born where 26
1:35:57	billion cells each one of those cells knows what it is and what it has to be 80 years later it and its descendants
1:36:04	and over time what i'm saying is aging is caused because cells lose their packaging and then eventually cells lose
1:36:10	their identity disease ensure ensues cells check out they become zombie-like
1:36:16	and they're now in essence right senescence and then our organs fail and we die but until recently we had no idea why
1:36:23	that was happening and so why is it happening well so the the packaging is the really
1:36:29	important part because much like the software runs the code the epigenome controls which genes are on and off
1:36:37	and if you stress the system and by that i mean biological stress and the biggest stress you can cause to a cell is to
1:36:42	break its chromosome because it's going to die if that if it doesn't fix it or worse for the body you get a tumor so the cell
1:36:49	has to hunker down stop dividing arrest just about everything it's doing and then try to repair that broken dna
1:36:55	but in doing so it has to do two things first of all it has to take proteins from somewhere else that are doing a
1:37:01	good job keeping the cell from functioning or making sure the cell's functioning correctly and those proteins are used by
1:37:07	the cell to repair the dna that's broken but also what's happening at the break is that that's all opening up as well
1:37:13	because you remember if you break a dna and it's spooled up you can't fix it you can't
1:37:18	glue it back together unless you unpack it stick it back together and then you've got to repack it
1:37:23	so this movement of proteins and the unpacking repacking of the dna i believe leads to cells losing that
1:37:30	original youthful what we call a gene expression pattern of how the genes are turned on and off and nerve cells as
1:37:36	they get older lose their ability to stay nerve cells and liver cells lose their identity as liver cells
1:37:43	all right so do proteins the way that you're talking about them sound like little creatures
1:37:48	i think of them because of my background like powder like just sort of inert
1:37:54	molecules which clearly judging by the way that you're talking about them they're not i've seen them animated before as having like articulatable
1:38:00	shapes and they actually move is that accurate that's essentially it it's it's super
1:38:06	exciting when you realize that proteins aren't just blobs or powders in the cell they're actually little little machines
1:38:13	like pac-man that go around and they can change the function of other things they can package the dna
1:38:18	and what they they do is they create chemical reactions that normally would take a billion years to happen
1:38:24	this is what an enzyme does it accelerates reactions and so we've got about twenty thousand different types of
1:38:29	enzymes in the body and they do different things but what we've discovered over the last 20 years
1:38:35	is there are certain types of enzymes that help package the dna and help with the dna repair these are
1:38:41	the ones that doing the ping pong game and without those we're screwed we basically will will age
1:38:48	more rapidly conversely what's really exciting is is we've discovered that you can make them
1:38:53	more active to make sure the dna is packaged correctly and the repair is very efficient and
1:39:00	there are ways you can do that exercise dieting being hungry they allow these enzymes that control
1:39:07	our body and make us healthier they make those enzymes much more active so instead of a pacman doing this
1:39:12	you exercise your diet take them take a molecule that we work on and it'll go around and fix
1:39:17	everything much more efficiently and keep you younger for longer we think why do you use the pac-man analogy which makes me think of it's eating something
1:39:24	is that what's happening is it eating cells that have a level of senescence or is it uh more bob the builder and it's
1:39:30	going around tearing some things apart putting some things back together yeah it's more like bob the builder but i
1:39:36	think a good example for at least the enzymes that we work on called sirtuins that protect the body
1:39:42	they're like a little tiny pair of scissors they chip up clip off chemicals
1:39:47	called acetyls and in doing so when they clip off the acetyls off those packaging proteins the dna gets more compact and
1:39:55	that's called gene silencing and over time as we get older and through this dna
1:40:00	damage process the sirtuins get inactive they're distracted by dna repair and the
1:40:06	packaging of that dna that that hose spooling starts to loosen and now genes that have
1:40:12	no business being on in the brain come on and partly i believe that's why we we have these diseases of the brain
1:40:19	[ __ ] that's so interesting um okay so one i want to know from a lifestyle
1:40:24	perspective what are we doing that's speeding that up and then two
1:40:29	what can we do from a lifestyle perspective to begin slowing that down or reversing it
1:40:35	well so i've been studying these enzymes the sirtuins we have seven in our bodies i've been studying them for about 25
1:40:42	years and what we've learned is that they respond to the cellular environment
1:40:48	there's a chemical that they require for gas think of them as the fuel called nad
1:40:53	and there's another molecule that is like the accelerator on the enzymes uh that makes them going even faster and
1:40:58	that's one of them is called resveratrol which we discovered years ago from red wine and together they actually do
1:41:04	really great things on these enzymes and make them keep the body younger at least for 25 years we've been studying mostly
1:41:12	animals and even little fungi yi cells and what we've learned from those studies is that
1:41:18	these are largely involved in responding to when organisms are under threat of survival
1:41:25	so how do you make the body feel like it's under threat adversity so one is run a lot or at least become
1:41:31	out of breath you know a few times a week your body will say oh man we had we had to outpace one of those
1:41:36	saber-toothed cats again gotta build up the body um the other is to be hungry
1:41:42	either a couple of times a week or every day you know skip a meal or two and then your body will turn on these sirtuins
1:41:48	make more of that fuel nad for the enzymes and we think that's what's
1:41:53	in part responsible for the health benefits of those uh lifestyle choices all right one thing though that you talk
1:41:58	about that i found really interesting is this notion of what may be good for you when you're young may come back to bite
1:42:05	you in the ass when you're older yeah so it's like the whole notion of hormesis that a little bit of bad is actually
1:42:12	extraordinarily good which is exactly what you're describing now get out of breath do all the stuff and so when the
1:42:18	information started pouring out that the only thing across every known um living
1:42:23	organism that extends lifespan is to eat less which you talk about in your own book it feels like you're saying to do
1:42:28	it for that reason just don't put as much stress on the system but now i hear you saying no no what you actually want to do is stress the system won't that
1:42:35	stress of i just ran from a lion a [ __ ] i'm starving won't that begin to stack up
1:42:41	and become problematic well actually if you step on a snail it's going to die so
1:42:46	there's certain amounts of stress that that you don't want to do but what you want to do is get the body to fear adversity and the
1:42:54	future but not enough to cause lasting damage or the unspooling of the dna that'll lead to disease and eventually
1:43:00	death so you you don't want to overdo it you want to be a little bit puffed you want to be a little bit hungry but of
1:43:06	course starvation malnutrition is not going to make you live longer so it's a fine line and what we've learned from
1:43:11	many animal studies and increasing numbers of clinical trials in humans is that you want to pulse it let the body
1:43:16	recover not constant we used to make animals go hungry all their lives and it worked but it actually works better if
1:43:23	you let them recover and i think that's that's the secret then let's really dive into that so i'm guessing you're talking
1:43:28	about where um animals were denied something like 20 to 30 of their caloric intake for very long periods of time is
1:43:34	extending their life by what like 30 or something um so super interesting but you're saying that if their caloric
1:43:41	intake over a long period of time is roughly the same of an animal that's just allowed to eat until it's satiated
1:43:47	that if it's done in a pulse pattern of hunger and almost over feed
1:43:53	they actually have the same benefits as the animal that has a chronic deficit of calories
1:43:59	all right well well let's be clear nobody knows what the perfect diet is even when it comes to fasting it's all
1:44:04	largely based on rodent studies so what i can tell you about the rodent studies which i'm very familiar with
1:44:10	is that if you take a rodent and reduce its calories by 25 for its whole life
1:44:16	it will live longer 30 but it'll be really miserable and aggressive uh and that's true for us as
1:44:22	well i've tried calorie restriction for about a week and i gave up i was pretty angry but what we discovered our my
1:44:28	colleagues um discovered is that if you it's not just what you eat it's when you
1:44:34	eat that's important and what's been found is that if as long as you have that period of hunger
1:44:40	um in a mouse so you can feed them every other day then they can gorge themselves as much as they want and they do they eat about
1:44:46	90 of what a mouse having free access to food would eat
1:44:52	but they they have the same longevity benefit as a mouse that's always been hungry and if
1:44:57	that's true what that means is for us is that we can enjoy life as long as we have that period of hunger once a day or
1:45:04	maybe twice a week and i believe the only reason we age
1:45:09	you know we could live for a thousand years otherwise the only reason we age is that our repair systems
1:45:15	become complacent you mentioned that what what is beneficial for you when you're young come back to bite you when you're
1:45:21	old what we think is that these repair systems are very good when we're young so the idea is it's called antagonistic
1:45:28	pleiotropy and i think it's right and that is that we evolved to stay healthy and alive and fit till we're 40
1:45:35	and then the forces of natural selection decline after that because we've essentially bred
1:45:41	we've often had children but we don't need to stick around beyond that and building a body that will last
1:45:47	a thousand years is pointless at that you know so most species only live as long as they need to to reproduce and
1:45:52	then a little bit more if you're a mouse that could die within two years they only build a body that
1:45:58	lasts two years if you're a whale that has no predators you can live for a couple of hundred years that makes more
1:46:03	sense why why does the whale live for a couple hundred years like i would say it's
1:46:09	pretty safe to say certainly um at some point in our past we became a pretty clear apex predator it's not that things
1:46:15	couldn't take us out but i mean by and large obviously look at how far we've come they didn't so why would we only
1:46:22	live to 40 is that whales continue to breed and be useful in that sense so that's really super interesting and
1:46:29	very few people talk about this the reason is that we were not at the apex of the food chain until recently
1:46:36	but in a world where we typically would die from starvation or from war a lot of men didn't make it to 40 because of that
1:46:43	we were at the middle of the food chain only now we we actually barely have a chance of dying
1:46:49	before 70 or 80 unless we're unlucky give us another 5 million years of
1:46:54	evolution we could evolve 200-year lifespans that's what should happen if evolution continues
1:47:01	a whale has been at the apex for about 30 million years and they've been
1:47:06	allowed to evolve those long life spans we are just like them we share most of their genes they're warm-blooded they
1:47:13	produce milk they're conscious they're basically us in the sea so anyone who says we've reached our maximum limit
1:47:19	doesn't know what they're talking about you and i have to eat 30 percent more
1:47:24	calories every day just to make our normal amount of atp
1:47:30	and you go well why would i do that well it turns out generating heat is what those
1:47:37	calories do and you and i are warm-blooded animals