2022-04-12 - Dr. Richard Miller - Longevity Supplements - Interventions Testing Program Results

Length: 1:21:40
Interviewee: Dr. Richard Miller

Dr. Richard Miller runs one of the labs for the Interventions Testing Program or the ITP, which is largely considered the gold standard for testing longevity drugs.

This was one of the best conversations I’ve had on longevity supplements that affect lifespan and those that might me subject to mere hype. Dr. Miller is rigorous in his approach and states the data clearly. He also has opinions on lifespan vs. healthspan that are unique from those of most others and worth paying attention to.

I genuinely walked away having learned so much from this conversation and feeling more awakened, and I hope it is useful to you too in parsing the data out there on longevity supplements.

In today’s episode, you will learn:

The 4 winning drugs that increase lifespan in mice as tested by the ITP: Rapamycin, Acarbose, 17-alpha estradiol, Canagliflozin
3 other drugs that produce small lifespan benefits: NDGA, Glycine, Captopril
Drug combinations: Rapamycin + Acarbose, Rapamycin + Metformin
Drugs that show no lifespan increase in mice in the ITP: Resveratrol, Nicotinamide-Riboside (NR), Fisetin, Curcumin, MCT Oil, Green tea extract, Fish Oil + more
Richard’s thoughts on lifespan vs. healthspan

Transcript

Welcome to Live Longer World!

0:00	we're just about to submit a paper in which we've combined two drugs rapamycin
0:05	plus a carbos and that that gives us the best percentage increase in males we've ever
0:12	seen we're getting about a 29 increase in males a carbos did not
0:18	improve on rapamycin effect in females so this is a combination of drugs that
0:23	is working better in the male mice than the female mice even though rapamycin by itself tends to give a
0:31	greater greater numerical effect in female mice than males hi everyone welcome to live longer world
0:38	a podcast where we unite to fight aging and boost longevity
0:44	all resources and premium member benefits can be found at livelongerworld.com
0:51	now on to today's episode my guest today is dr richard miller who

Richard Miller Intro

0:56	runs one of the labs for the interventions testing program or the itp which is largely considered the gold
1:04	standard for testing longevity drugs this was one of the best conversations
1:09	i've had on longevity supplements and in trying to figure out the ones that actually affect lifespan and noise
1:16	versus those that might be subject to mere hype some of the supplements we spoke about
1:22	include rapamycin a carbos rapamycin plus a carbos metformin fish oil
1:29	curcumin sulforaphane green tea extract and what have you
1:35	i genuinely walked away feeling like i learned so much and feeling more awakened from this conversation and i
1:42	hope this is useful to you as well in parsing out some of the data on longevity supplements and drugs
1:50	hi dr miller and welcome to the leblanc world podcast glad to be here

Richard Miller Wildlife photography

1:56	happy to have you you're one of the best people to talk about longevity supplements you know there's so much
2:02	hype around uh some of these supplements and i think you're the one who can actually uncover
2:07	some of the data for us and maybe bust some of the hype or the myths around it
2:12	but before i dive into some of the longevity drugs and you'll work on the itp
2:18	um i have to say i saw some of your photography on wildlife and landscapes
2:25	and i was blown away they're just stunning so i'm curious did you
2:31	is this something did you start photography at a young age or was it did you pick it up later in life
2:36	and did this in any way shape or form influence your interest in science or longevity
2:43	yeah i picked it up at the young age of 55. it's just a good way to spend vacation
2:49	time you get to go to interesting places with interesting people i used to do mostly birds and now i do mostly
2:55	uh landscapes and animals but it's it's uh it's fun i mean the covet thing is
3:00	cut into that because international travel is now a great deal more difficult i i can't wait to go to go
3:06	back i've been going to places in the united states and that's good too but they don't have the same things that they have in kenya or japan for instance
3:15	yeah they're just gorgeous and i'm gonna link to uh link to your pictures in the show notes
3:20	as well so everyone else can be amazed actually send them to a few friends and i said these are fantastic
3:25	um yeah um so you work on the itp of the

ITP - the gold standard for testing longevity drugs & winning drugs

3:31	interventions testing program which is largely considered the gold standard for testing longevity
3:38	drugs maybe before we dive into some of the specifics or talk about some of the
3:44	supplements or drugs you've actually tested if you can explain what is the interventions testing
3:50	program how does it work sure about 20 years ago hubert warner who was
3:55	at that time the head for the biology people at the national institute on aging thought it might be about time to
4:02	have an organized multi-institutional program to see if adding drugs to mice would extend their
4:09	lifespan and slow a very wide range of age-associated diseases so he put
4:14	together a small committee about 20 people we had a conference came up with some ideas
4:19	and the initial grants were made to three institutions
4:24	18 years ago the drugs are suggested by anyone in the world including anyone who's listening
4:31	to your program there's a once a year competition people can describe what drugs they think ought to
4:36	be tested and why and then the drugs are tested in three separate laboratories mine at the university of michigan randy
4:42	strong's at the university of texas in san antonio and at the jackson labs in a program headed there by david harrison
4:50	and nadia rosenthal we do it at three locations because that
4:55	way we sort of have if we're lucky built in replication if we see a drug
5:00	that is producing good strong lifespan benefits at all three sites then we know that despite site-to-site
5:06	variations the drug is likely to work when it's tested at someone else's site as well
5:14	we sometimes however find the drug produces perfectly good results at one of the three sites but not the other two
5:20	we publish that also but at least the people who read that report are aware that um
5:26	there are still some variations that uh control the ability of the drug to extend lifespan in ways we don't
5:32	understand so we screen five to seven drugs new drugs a year and most of them don't work of course
5:39	it's very hard for people to guess here's a drug i'm pretty darn sure it's going to
5:44	improve mass longevity most of those guesses even by very smart people are just wrong
5:50	but we have had at this stage four published drugs and two more that are unpublished that give strong
5:57	benefits and when i say a strong benefit i mean a lifespan exchange of 10 or more
6:04	to put that into context uh jay o'shansky published and his colleagues published in science in 1990
6:11	a paper that calculated for human beings what would happen to the average lifespan if there was no more cancer
6:19	and the answer is about a three percent lifespan extension and in the same paper they showed that if you have no more
6:26	heart attacks the average human lifespan goes up about three percent
6:31	so people who were going to be dying at the age of 80 they live another two and a
6:37	half or three years they're dying instead at 82 or 83. so the four drugs that i've mentioned to
6:43	you give a 10 or more up to we're now up to 29 but at least a 10 increase in longevity
6:51	that is about three times the effect you would expect to see in people by a drug
6:56	that was a complete cure for cancer so in terms of their potential impact on
7:02	healthy human lifespan these winning drugs um
7:07	could well be of great importance and great interest the other things that are
7:13	i think major benefits for the itp are are twofold one is
7:19	sort of broad and con conceptual most people about 20 years ago or even
7:24	30 years ago were pretty darn sure you could never have a drug that i slowed
7:29	aging was very very complicated and the aging of the eyes the age of the ears the aging the brain and the skin all
7:34	that is under its own separate control so that the search for some way to slow the aging process was hopeless it was
7:41	doomed to failure in fact there were six page editorials in nature as
7:46	recently as 1993 proving that you could never have a single gene or a single drug that
7:53	extended lifespan and interestingly uh it was only three or
7:58	four months later that the first single gene mutation that extended one life span was published by cynthia kenyon and
8:04	her group so the itp data show i think convincingly to anyone who pays
8:10	attention to it that that old idea was just wrong that although aging certainly is very
8:15	complicated in its ramifications very complicated in its effects there have to be there are indeed
8:23	some pathways in mammals and animals built just like us that you can
8:29	mess with in ways that will uh postpone a very very wide range of uh
8:34	age sensitive diseases and disabilities and inconveniences including those that lead to death and therefore the drugs
8:42	extend lifespan changing the the conceptual framework for that is i think a major step forward because
8:49	people won't want to look in that question if they think it just cannot be addressed the other is more technical
8:55	and that is that each of the drugs that works gives scientists strong indication of where the most
9:02	fruitful searches would be so the first such drug that we published rapamycin affects a specific enzyme an
9:09	enzyme full tour and that has i think quite justifiably uh encouraged many many people to start
9:16	looking at what does tor do what happens downstream of torah what is upstream of two or what drugs can change or
9:22	similarly two of the drugs that we've published more recently one called a carbos and one called canagliflozin
9:30	they both affect something very specific the highest level of glucose you can get in your blood they don't affect the
9:36	average daily glucose what they do is they affect how high the peak is and one does it by working in the gi
9:43	tract the other does it by working in the kidney but they both do it and both of them lead to
9:48	life span increase in males only for reasons we don't understand
9:53	that's an implication that if you would like to know how to slow down aging and in particular if you'd like to know how to
9:59	age-associated cancers um take some a lot of attention to what the
10:05	peak daily glucose is doing how that's involved in these um
10:11	broad-spectrum multi-disease uh aging sets of aging uh sequelae so
10:17	every time the itp develops evidence for a new drug it opens a whole
10:22	new set of productive pathways for people to understand more about how
10:28	the targets of that drug might be critically related to a very wide range of diseases and
10:34	through changes of aging potentially lead to retardation of multiple diseases
10:40	right and the first point you mentioned i mean i think a lot of people are still coming around to the fact that aging is
10:46	in fact malleable you know and a lot of these drugs show that rapamycin is one i'm very excited about

Rapamycin, Rapamycin + Acarbose

10:53	too i spoke to matt cabellon who's also now starting studies on humans uh people
10:59	who are just taking rapamycin experimenting with it so i'm curious what did the results say for rapamycin
11:06	what was the lifespan extension um and also were there sex specific
11:11	differences for rapamycin and what was the dosing schedule
11:17	well those are four different questions so um we originally tested rapamycin at a
11:23	specific concentration of 14 parts per million of food that is 14
11:28	milligrams for every kilogram of food and uh it led to like i'd have to look up the paper to give you the second
11:34	decimal point but it's about uh 20 and the female is about 15 of the males
11:40	it suggests that uh incorrectly suggests that it may have a preferential benefit
11:45	on females the reason that would be an unwise assumption is that uh work done by randy strong and
11:50	his collaborators in texas found that at any given dose of rapamycin in the food
11:56	the blood levels are higher sometimes three times higher not just subtle but a big difference in the females
12:02	so when you give a graph always at a given dose in the chow you're actually giving a higher dose in terms of the
12:09	blood concentrations to the females when you use rapamycin by itself
12:14	that higher doses the best we've been able to get in females about 26 percent
12:19	and that same high dose produces about a 23 percent increase in male mice we're just about to submit a paper
12:26	in which we've combined two drugs rapamycin plus a carbos and that that gives us the best
12:34	percentage increase in males we've ever seen we're getting about a 29 increase in males
12:40	a carbos did not improve on rapamycin effect in females so this is a combination of drugs that
12:47	is working better in the male mice than the female mice even though rapamycin by itself tends to give a
12:55	greater greater numerical effect in female mice than males
13:00	do you know why there are these sex specific differences do we know anything about it no
13:06	i mean there's a lot more to be done by pharmacologists the most plausible guess has to do with
13:13	distribution of the drug into different tissues some drugs are for instance sequestered in the fat and then slowly
13:19	released over the course of the next day or the speed with which they are conjugated and then made available for
13:26	either degradation or excretion in the urine these any one of those steps could well
13:33	be different between males and females in ways that
13:38	modify the average blood concentration of rapamycin certainly these are things you'd want to
13:44	know a lot about if you wanted to see if any of the stuff worked in people
13:49	right and in terms of at what age you take these therapy mice and a carbos i
13:54	guess in mice you're testing them at middle age is that correct oh
14:00	no no it's not i mean um we have tested rapid in the initial papers we actually tested dropping mice into two different
14:07	uh ages um the young group got rapamycin starting at nine months of age
14:13	which in terms of the percentage of your lifespan completed is like the equivalent of a 30 or 35 year old person
14:20	they're healthy young adults but almost none of them have died at that age but another group got rapamycin at 20
14:27	months of age and in terms of percentage lifespan uh completed that's sort of the
14:32	equivalent of a 55 or 60 year old person a small fraction of them have died a
14:37	small fraction of them are sick but probably 80 or 90 percent of the animals
14:42	are still alive at that age we anticipated that if you give the rapamycin starting at an earlier age
14:50	you'd get a bigger effect i really thought that would be the case but it isn't one of the biggest surprises we've ever
14:56	seen in or i've ever seen in an idp data set was that starting at nine and twenty
15:01	months at age four at the mice game the same result the same amount of
15:07	increase in median life span and in the age of death of the longest live 10 so
15:12	it's it doesn't just peter out at a certain age that suggests strongly that there are
15:18	rapamycin sensitive events occurring even in animals that have completed two-thirds of their lifespan
15:25	of their expected lifespan that are rapamycin sensitive and can be used to
15:30	postpone all sorts of diseases including the lethal diseases to a substantial extent
15:37	we've answered that same question now for two other drugs for a carbosome for 17 alpha estradiol
15:44	if you start a carbos in middle age you get half the effect it still works
15:50	but it in terms of the percentage increase in lifespan it's only half as good as if you started in the younger
15:56	animals for seven younger animals here being nine months or even younger
16:02	for carbos it would be i think we started in four months so i'd have to look it up to
16:08	be sure and then 17 alphester dial if you started in 16 months it is very good
16:14	it's still male specific it only works in males but even when you start in 16 months it's just about as good as if you
16:20	started it in uh nine and ten month old animals you can even start it as late as
16:26	20 months and you get a significant increase we've also evaluated gravomycin starting
16:33	at old age with different dosage regimes in the experiment which was just published some of the mice got rapamycin
16:40	starting at 20 months of age and then for the rest of their lives and in both sexes
16:46	you've got to benefit exactly the way we would predict others of them got rapamycin in an on off on off so they
16:54	got it for one month on one month off one month on one month off for males this
17:00	cycling thing worked great it was just as good as having it every single day
17:05	for females it was about half as good it worked but it wasn't as good as leaving the stop in there all the time
17:12	and the third dosage regime was we gave it to the mice when they were 20 months of age for just two months
17:19	and then we took them off we gave them a pulse for males it worked great it was just as
17:25	good but for females it only works half as well we don't know why it would be
17:31	nice to know i would love to know right it may well be different in
17:37	mice and humans the dogs these are likely to be um
17:42	molded by sex specific enzymes and sex specific excretory pathways that are
17:48	probably going to be quite different from the in every species and what was the reason for picking
17:54	monthly dosing uh did you think to do maybe weekly dosing testing as well
18:00	it was arbitrary we just said let's try on off on off or off and we said let's let's change it every month on the first
18:06	of the month it's easy to remember we don't know if it's the best we don't know it's the second best it's just what we tried but one of the problems is when
18:13	you have a winning drug and we rapamycin and carbos and canagaflozen and seventh estradiol are all winning
18:20	drugs in that sense um there's an awful lot of cool stuff you really want to do you want to start it
18:27	in youth and then turn it off when they get to be middle-aged or you want to give it uh once a month and then
18:33	uh repeat again one month and you want to try all these different variations and
18:38	that's too expensive so we we pick a couple of variations that we think are most likely to be
18:43	informative and we give those a try so rapamycin and a carbos uh the

Rapamycin + Acarbose Dosing Schedule

18:49	combination of the two you said you tested those as well what was the dosing schedule for that
18:55	uh we gave rapamycin plus a carbons starting from nine months of age and we gave it every day until the mice died
19:02	when you do that you get the longest lived males we ever got and we get females that live just as long as
19:09	rapamycin by itself would do for them we also did that at 16 months of age and it
19:15	was a little puzzling for 16 months of age for females to work great for 16 months of age at males it didn't
19:23	it didn't work at all or it did just barely really it was significant statistically but it was a
19:29	disappointingly small effect and we don't know why in our class in our in our
19:35	itp labs the males are not as long-lived as the females and it's possible that
19:40	starting at 16 months is just too close to the a expected age of death for a lot
19:46	of the male mice so it may be asking an awful lot of rapamycin started that late
19:51	in male mice to have a big effect it did so in our 2009 paper but this time
19:57	around it did not that it was as good as rapamycin but no better right
20:03	and are you thinking of combining maybe rapamycin and estradiol or um some of
20:08	the other i know you're probably thinking of combining rapamycin and metformin for the new cohort
20:14	so those are two questions um i think combinations of drugs are a good idea in

Combination of drugs, Rapamycin + Metformin

20:19	particular if people have a biochemical rash now for thinking that
20:25	the two may have non-overlapping side effects or non-overlapping pathways that lead to
20:30	benefit or if one opposes the side effects of the other all of those are good
20:36	rationales we we are always dependent on the scientific community to propose to
20:41	us combinations of drugs and in fact the last group of proposals that came in that
20:47	quite a number where somebody said test drug x plus drug y and hear what here's why i think it's
20:52	a good idea you mentioned in particular rapamycin plus metformin we actually did test that
21:00	and the results were um a little hard to interpret metformin had
21:07	no by itself has no effect on mouse lifespan no benefit at least at the dose we tested it's possible that at some
21:14	other dose it might have been good but if the dose we tested uh it had no benefit by itself
21:20	now when you combine it with metformin i'm sorry with rapamycin so you have
21:25	metformin plus rapamycin it gave a slightly increased lifespan in
21:32	the males but it was not statistically significant so um
21:37	we can't say look we've got strong evidence that the two put together do better than rap and bison by itself
21:44	there's a sort of a hint that that might be correct but it didn't rise to the standards
21:49	expected for um strong conclusions so we published it and people can draw their own conclusion
21:55	okay so going back to the four winning drugs that you spoke about you said that icobose what's it what it's doing is

17-Alpha Estradiol

22:04	blunting the peak glucose levels it's not just about keeping it i mean your glucose levels to
22:10	a certain level it's about blunting the peak level what about estradiol what is the
22:15	mechanism by which you think it acts as a longevity supplement [Music] that's a very good question and we
22:22	really don't know and we would love to know everybody knows about 17
22:28	beta estradiol it's people call it estrogen it's a very famous sex hormone
22:33	higher levels and females so 17 alpha estradiol which is what we used
22:39	is very similar but one of the hydroxyl groups points up in the opposite direction
22:44	so for that reason it does not do a great job of binding to the classical estrogen receptors and it's relatively
22:52	non-feminizing they're i'm no expert in this but it's either 10-fold worse or 104 worse at stimulating uh estrogenic
23:00	effects in mice so we gave it to the mice in the hopes
23:05	this was a reasonable idea but it was wrong the hopes that it would move the lifespan of male mice
23:11	to the same slightly higher level that female mice get on their own
23:17	in fact it didn't do that it did much better that is male mice given 17 alpha estradiol have life span
23:25	changes that push them way better than female mice whether the female mice are on the drug or not the
23:32	drug has no effect on females for lifespan and females so we don't know what the target is we
23:38	don't know whether the target is a cell in the brain or a cell in the pancreas or some on the liver or something we
23:44	have one important clue which we're now following up on mike garrett who was in my lab at the
23:51	time collaborated with a guy named mo jane uh who was a an expert on metabolomics and
23:57	he gave mo the tissues from these mice he said what has changed in the steroids and
24:03	there was a very interesting response there are a couple of steroids that are related to 17 alpha estradiol they're in
24:10	the estriol class and they went way way up in the male mice that got 17 alpha
24:17	estradiol they went up 20 fold but they didn't go up in females
24:22	so when you have a male mouse and it gets 17 alpha estradiol the chemical we give them
24:29	suddenly these estrogens shoot to the sky and that's a male specific response
24:35	apparently only the males have whatever enzyme it takes to turn the 17 alpha
24:40	estradiol into the s estriol derivatives so the
24:46	best guess is that it is that but that's the good stuff the estriol produced by males only may be accomplishing the
24:54	health benefits that you see in the males only so the obvious experiment to do which is the one we're
25:00	now doing is to give both male and female mice the estrogen and if in fact these estrogens are the
25:08	active ingredient the product of metabolism of symmetry alpha estradiol
25:13	then they might work in both sexes that's certainly our hope but we don't know where the target is um
25:19	it's a reasonable guess that it's having some effect on one of the many uh
25:26	uh parts of the brain that regulate metabolism and health but that's not saying very much and clearly there's a
25:33	whole world of experimentation that needs to be done to sort of nail down specify and then test that
25:38	idea absolutely so what's the fourth one then we've discussed uh rapamycin acrobats

Canagaflozin

25:47	you know we published canada frozen last year um this is a drug that's given to human diabetics and it's
25:55	become a very popular drug in the last few years each of the major companies makes a version of it
26:01	different chemically but with the same target the way it assists diabetics is it affects
26:06	reabsorption in the kidney of glucose so that um you know it's very dangerous
26:12	for diabetics to have a high glucose level in their blood so what the when the glucose goes really high in the
26:18	blood it tends to be lost by the kidney if this drug is
26:25	present it poisons the part of the kidney that reabsorbs glucose
26:31	and so it's harder to get glucose way way way up if you've taken cannabis lows you can
26:37	see why this would be good for diabetics so there are hints here and there in the
26:42	literature a few papers on cancer and a few papers on heart attacks
26:47	and strokes suggesting that in addition to the benefit canagosthosis has on
26:53	diabetic people it may have subsidiary benefits for cancer for strokes for heart attack
26:59	for a lot of other stuff in any case our mice are not dying of diabetes they don't get diabetes about
27:04	80 of them are dying of some form of cancer there are many kinds of cancer in these mice but about 80 percent of the
27:11	deaths are attributable to cancer canigos flozen by is extending lifespan
27:18	of the male mice and is doing so presumably by inhibiting cancer plus a lot of other bad things
27:25	that happen to mice whether it's doing so by blocking peak glucose that's our guess
27:32	or whether it's that plus something else we would need to sort out we've just
27:37	completed a study we haven't published it yet involving a collaboration with two
27:43	experts at the university of washington on veterinary pathology warren latagus and jessica snyder
27:50	they were given um animals that had been euthanized at 22 months of age half of them on
27:56	canadian flows and half of them not on trinidad's closing and they found seven kinds of diseases one in the
28:03	adrenal one in the heart one in the vessels one in the liver one of the kidneys um
28:08	and one in the pancreas that went up with age uh in both sexes
28:14	and canada flows and blocked them but in males only so it's clear that
28:21	the ability of kaningothalosin to extend lifespan in males
28:26	is accompanied by and one would guess caused by its ability to block a very large range
28:32	of age-associated pathological changes now why that is seen only in the males
28:39	is uncertain so it sounds like a kerbos is doing the same thing as well right
28:46	both in terms of blocking peak glucose levels yeah that's i think the best guess the
28:52	reason we wanted to test the negative was to see whether the carbons benefit
28:58	was due to the blockage of peak glucose a carbos
29:05	produces it by an action in the gi tract to slow the absorption of glucose and canaglyceosis
29:11	instead alters absorption reabsorption of glucose by the kidney
29:17	so since they both work and the one thing they really have in common is their ability to interfere with the highest
29:25	levels of glucose after the mice eat a big carbohydrate meal it's a reasonable guess that is the
29:31	inhibition of peat glucose that is the critical thing but we don't know why that's male specific
29:36	and we don't really know how inhibition of glucose can inhibit cancer and vessel changes
29:43	and heart changes and kidney changes and adrenal changes all of that needs to be worked out
29:49	do you know if there could be any side effects if non-diabetics are taking these two drugs
29:55	oh i don't know i'm not an expert in that but in diabetic patients both drugs
30:01	are are thought to be really quite safe there's a side effect from a carbos
30:07	because it changes the bacteria in your gut it tends to make you flatulent and makes you have a
30:13	particularly if you eat wheat as your main carbohydrate source it tends to produce gastrointestinal upset
30:21	that's one of the reasons why the drug is more favored in countries
30:27	where rice is the principle carbohydrates so it's countries like india parts of china other
30:33	asian countries where rice is the main carbohydrate source a carbon is a lot more popular
30:39	because it doesn't tend to produce bloating right i i grew up eating a lot of white
30:44	rice um fantastic um one question i had is what
30:49	was the lifespan extension you saw with canagoflezen and at what age was it given to mice
30:57	well in the initial studies again i'd have to look it up i think we started at six or seven months of age in young
31:03	adults and the percentage lifespan extension in the males was i think about 15
31:09	we would certainly like to know whether it will also have a benefit when you start at a later age so we now have some
31:16	groups of mice that are getting connect with loneliness and starting only at 16 months of age as late as 16 months of
31:23	age and it'll be a year or more before we know whether it has the same benefit zero
31:28	benefit or something in the middle okay so do you take any of these for winning drugs

Does Richard take the 4 winning drugs?

31:35	yeah i'm not going to talk about that um but people when people ask that question is they're asking
31:42	secretly should i take them should my friend take and i'm not a doctor and the correct
31:48	legal and i think ethical answer is to say if you think these are good for you should talk to your doctor and see if
31:53	you and your doctor agree on on these matters uh each individual person will have
31:58	his or her own risk tolerance uh ideas about how important
32:04	it is to take specific drugs and a physician physician's opinion needs to be consulted
32:10	absolutely no um all right so we've decided we recommend green vegetables and exercise
32:16	and not smoking 100 for sure yes um okay so we've discussed the four
32:22	winning ones um that you you spoke about the data there what about some of the
32:28	ones that don't work and i do want to discuss that because there's just so much controversy around some of them for
32:34	example um resveratrol is one and then before we get to that i i told you the four that
32:41	had the biggest effect but we have um three others

3 Drugs that have small lifespan effects & promising

32:46	which produced significant effects and which could well spark interesting new research okay yeah
32:54	let's talk about this was a molecule called ndga it's nor dihydro guyaretic
33:00	acid ndga it works three times in a row so it really really works but it only produces
33:05	about a 12 percent increase in lifespan and it's male specific it's quite expensive and so
33:11	once we had other things that worked better we haven't really been studying in dga but
33:17	it clearly has some effects what is it what does it do it's an antioxidant
33:22	and it has anti-inflammatory properties so we don't know whether the benefits are
33:28	because it's an antioxidant or because it's anti-inflammatory or because of both or because of neither but it has
33:35	been studied in the past as an antioxidant and as an anti-inflammatory
33:40	the second is is a famous amino acid glycine if you put an enormous amount of glycine
33:47	to the diet that six percent of the weight of the diet is glycine it produces a small benefit now the benefit
33:54	is seen at all three sites is seen in males and females it affects both the average lifespan and the
34:01	lifespan of the oldest animals so it's really really there but it's small it's only about five percent
34:07	so um again we have put that you know
34:12	to the back burner so to speak because the effect size is quite small and uh we have other things which have a
34:20	bigger effect the last of these which is not published which will be submitted for publication
34:25	i hope in a couple of weeks is an anti-hypertensive drug called captopril it's it's used in people as an
34:32	anti-hypertension hypertensive the studies that we've just finished
34:39	used only a single dose and in the male mice it didn't produce a real benefit in
34:45	the females it did produce a real benefit but a small one about five percent
34:50	so my guess is and it's only a guess is that when we try higher doses of
34:56	captopril next year for instance when we try higher doses it may work
35:01	better in females may even begin to work in males so i'm i don't want to give up on it even though the initial results
35:07	were in one sex only and quantitatively kind of small you know it's a lead and uh
35:13	we don't think it's if it's working at all we don't think it's working as an anti-hypertensive agent but it may be working through
35:20	other pathways that deserve a lot of attention and are you going to test any of these
35:25	in combination with maybe some of the forwarding drugs yeah all of those would be good
35:31	ideas uh i think before i before we study something like
35:38	captopril plus rapamycin i'm going to be darn sure that captain pearl really works
35:44	i want to repeat the study at higher doses and see if we can
35:49	replicate and hopefully improve upon these sort of maybe they're maybe not there results
35:54	that we got when we studied it starting in 2017.
36:00	yeah and i think one of the things you mentioned is it's going to uncover some of the pathways that maybe we can study
36:06	so for future research it's going to be fantastic yeah if we use a higher dose and now we're getting a 20 increase in females
36:13	and a 10 increase in males then that will justify and help guide
36:19	much more intensive research into the targets and how they might be related to a variety of
36:26	of potential anti-aging mechanisms one of the things i didn't mention to you but i think is

GPLD-1 & shared mechanisms in longevity drugs

36:32	very important now that we have at least four drugs that slow aging
36:37	and at least two or three mutations of slow aging and two diets of slow aging for the first
36:43	time we can begin to ask what mechanisms do they have in common so some people in my lab for instance
36:49	are really interested in a molecule called gpld1 the liver produces it and it goes
36:56	to the brain and it improves uh production of new neurons
37:01	well uh this scientist her name is jenna lee li has found
37:06	that gpld1 is turned on by the mutant genes that's good and it's turned on by the drugs
37:14	that's good too so that suggests and and by caloric restriction so that suggests strongly that
37:19	it may be a major player in the prolongation of of life healthy lifespan
37:26	regardless of whether you're doing that genetically or pharmacologically or through a dietary manipulation if that's
37:32	the case then looking at drugs that specifically elevate
37:37	that protein will be a worthwhile pursuit the having at one's fingertips
37:44	multiple genes multiple drugs and at least two diets caloric restriction and methionine
37:50	restriction the extent lifespan for the first time makes it possible to look for shared mechanisms
37:56	figuring out how caloric restriction works has been an enormous headache for 70 years
38:02	because caloric restriction does so many things and proving that this one but not that one is the connection to aging has
38:10	proven very frustrating but now that we have multiple ways
38:16	quite different ways of slowing aging and extending lifespan at least in mice we can start to see what things they
38:22	have in common and that helps us very much focus our attention on plausible links
38:28	rather than just idiosyncrasies of each of the of the techniques we're using that's brilliant i haven't heard anyone
38:34	talk about or answer ask the question what are the shared mechanisms connecting mutant
38:40	genes and diet longevity diets and also longevity drugs so that's that's amazing
38:46	are there is there outside of gplt too um is there anything else that you notice
38:52	is shared among these three or maybe even among two of them that's what everyone in my lab does we
38:58	have several good leads i can mention them uh if if you think your listeners would be interested uh there's a guy
39:04	named joe endicott who works on chaperone mediated autophagy and he's found
39:10	with collaborators that there's high levels of chaperoning autophagy in
39:16	the mutant mice and also with three of the four drugs they also turn it on
39:22	there's a guy in the lab named gonzalo garcia he is interested in controlled translation that is selective
39:28	translation of some specific messenger rnas and he's found that they too are
39:33	augmented these selective rna transparent translation events are augmented by the drugs by all
39:41	of them a carbos rapamycin and 17 alpha ester dial as well as by the two mutant
39:47	genes uh interestingly both joanna cuts work and gonzalo garcia's work by not looking at
39:53	transcription they're not looking at what genes are transcribed from dna which is what most other people do
40:01	but at what happens in terms of translation which messenger rnas get translated into proteins that's
40:08	gonzalo's work and once the protein is there what things chop it up and throw it away
40:14	which is what uh gel and endicott is doing these non-transcriptional changes may be we
40:20	think a really important shared common mechanism and tying them together is the
40:26	gpld1 stuff that gina lee has done because the gpld1
40:32	turned on by the genes turned on by the drugs turns out to be one of those rare proteins whose translation is controlled
40:40	by the mechanism garcia is studying cap independent translation so that we didn't know that when we started but uh
40:47	jinnah's work has now shown quite nicely very exciting stuff that the
40:53	selective rna translation that we've been studying for other reasons which is characteristic of all sorts of slow
40:58	aging mice that turns out to be the trick for getting a lot of gpld1 in the blood uh
41:05	and and when placed in the blood neurone and genesis uh and brain cell health maintenance are
41:12	are augmented someone else discovered that but we've confirmed it so we could potentially maybe use some
41:20	sort of mrna techniques to turn that on as well and turn on gpl d1
41:27	yes uh what we want we have one already but we want a lot more we want a drug we
41:33	want 10 drugs selectively promote the translation of
41:39	these cap independent messenger rnas i no one really knows what fraction of
41:45	the mrnas can be translated in this way we have about 10 proteins that we know
41:50	are translated in that way um there may well be a hundred or 200 or
41:55	more but what we really want is a drug that will turn those on because gonzalo
42:00	has shown that uh they are turned on both in the slow 80 mutants and
42:07	in mice exposed to rapamycin a carbos and 17 alpha ester dial
42:13	it's interesting you know 17 alpha estrogen dial as we've mentioned is specific it only has a lifespan
42:19	benefited in the males gonzalo has found that it turns on this kind of translation in male mice only so that's
42:27	a really nice match for uh the health benefit which is also male
42:32	specific for that particular drug and you said this gpld1 is produced naturally by the liver
42:38	what is there something that's going on with age
42:44	it's known that it's produced by the liver jenna has found that it is also produced
42:49	by the fat and we don't know whether that's important or not but it is produced in the fat and in the
42:56	fat it is also produced by cap independent translation i don't know whether it changes with age the people
43:01	who are studying it both in mice and humans are really excited by it because it's turned on by exercise
43:08	everybody sort of understands that getting a lot of exercise is good for you and there are some
43:13	very well qualified labs that say yeah it's good for you because it encourages the production of gplb1
43:21	and in fact animals that exercise make more gpl d1 and it's there's more of it in their
43:28	plasma and there's at least speculation that that may promote healthy brain aging too that's someone else's work and
43:35	i don't i don't have the skills or the knowledge to say whether it's right or wrong but that's what they've concluded
43:42	in our work in the mice we noted that the anti-aging drugs turn on gpld1 and also turn on
43:50	two indicators of healthy brain aging we suspect that's cause and effect so we
43:55	haven't proven that yet fantastic that's a beautiful link i'm excited to learn more about it
44:02	all right um maybe some of the ones that don't work some of the longevity drugs that you've tested um

Resveratrol in ITP

44:09	one that i brought up was resveratrol what did you see in the itp lab
44:17	uh research had no effect on lifespan in mice we were told to test it starting at
44:23	young ages and middle ages like four or 12 months didn't matter we were told to test it at a high concentration and at a
44:31	very high concentration we did that it didn't matter then the group of rafa de cabo who
44:38	is at nih they tested it in normal mice it had no effect no benefit
44:44	uh rafa's group with david sinclair had published a very famous very high
44:49	profile paper uh claiming that residual extended lifespan in mice but
44:56	they used mice that were on a diet that had 60 coconut oil and
45:01	they didn't mention it at the time but these mice are really short-lived and what they're
45:06	dying of is a fatty liver the coconut oil concentration in their diet is so high
45:12	the liver expands and crushes their lungs the lungs get compressed
45:18	by this fatty fatty diet to the point where the animals cannot inhale they cannot breathe
45:25	so they are dying of coconut oil poisoning and resveratrol apparently
45:32	works pretty well for that if you are find yourself in a place where there's nothing to eat except coconut oil that
45:38	would be the circumstances resveratrol might be worth the clinical trial but um
45:44	it otherwise it's it's hard to say that it hasn't had any benefit in mice
45:49	i i don't know what happened in the human studies i know that there was a company called
45:55	certris that's appeared to be making great progress at developing
46:00	um sirtuin uh activators like research role they sold it to glaxosmithkline for
46:06	something like 600 million bucks and glaxo found that they could not replicate any of the findings and they
46:13	closed the that part of the company and took a 600 million dollar tax write-off
46:19	because the idea that certain activating agents was good for you was not something they could confirm
46:26	so the same is said for nr and nmn at least some scientists in the field would say

NR, NMN

46:32	that that's also activating serotonins uh did you try nrn in the lab as well
46:40	we published the itp published a paper we gave nr nicotinamide riverside
46:46	to mice and it had no benefit um we have not tried
46:52	nmn yet uh no one has proposed it to us
46:57	um i know that there are companies that are pushing it they've got beautiful websites a lot of glossy
47:05	bottles with ultra ultra pure stuff in it what i haven't seen yet is any evidence that
47:10	their stuff actually is good for you right because the fda will allow you as long as you don't say it treats or
47:17	cures or prevents a disease you can wink and sort of let people know yeah it really does but
47:24	you don't actually have to have any evidence for that so you can make a lot of money pushing the stuff but i don't know of any evidence that it's actually
47:31	good for you and no evidence in humans or in mice
47:36	yeah that's exactly what i was not a bad idea i mean right it's entirely possible
47:42	uh it's entirely possible that one or more of the members of that uh biochemical cascade including nr
47:49	and including nmn at some doses at some ages
47:54	may have health benefits in people may have health benefits and mice i have seen
48:00	a paper submitted for publication which involved one or more of those drugs in
48:05	combination with other drugs which seem to work together quite nicely i can't say anything more about it but i
48:12	i don't think it's a silly idea i think it's a great idea deserves very careful attention
48:18	what i am arguing against is um putting too much emphasis
48:24	on very sparse data sets and making claims for human health benefits that are not really supported by
48:30	evidence i don't think that's a great idea yeah and and that's that's why i'm asking you as well because you know a
48:37	lot of these companies sell the supplements for very high prices and um i i just say that well we should also
48:44	try to find the human evidence and the data so i think consumers should be given that information and that's all
48:52	yeah human evidence that a drug slows aging may well be very very difficult to get
48:58	it's entirely possible that you have to take some healthy young 30 or 40 or 50
49:03	year old people put them on the drug for two decades and see if it has a health benefit no drug company ever will want
49:09	to do that study it's much too expensive and the people who run drug companies need data within three years so that
49:16	their stock prices will stay up it will continue to go up uh nobody there wants
49:21	to invest hundreds of millions of dollars in a risky study that won't produce answers for 20 years
49:27	um on the other hand they can sell stuff that doesn't work as long as they don't call it a drug as long as they call it a
49:34	health supplement or something or a health food or something they can sell that and make billions of dollars
49:39	without having to have any evidence so that's that's the commercial path that that's the path that works well
49:44	it's possible that some of these drugs do slow aging even in people
49:51	and we may never know it uh from human studies human studies that
49:58	meet the fda criteria for approval if we're really lucky and i think this would be a
50:04	very tough bet to take but some people are thinking it's possible you could give these drugs
50:10	to people in their 60s and 70s for a decade and maybe just maybe it's slow
50:15	that they show that they have a diminished risk of alzheimer's a diminished risk of cancer diminished
50:20	risk of diabetes a diminished risk of stroke that the fda would be interested in
50:26	because any one of those things is authentically a disease and preventive medicines that prevent
50:31	those diseases would be fda approvable but this would only work this is an expensive study on its own it's i think
50:37	about a 50 million study as has been proposed for metformin by a consortium
50:42	of 11 universities it takes a while and you have to sort of hope that the thing
50:48	you're using will work even if started and people who are already quite old
50:53	that's right yep yeah the the metformin study i think is either ongoing or just about
50:58	historical i think it was halted because of coverage when i last spoke to dr neil barzillai who was conducting
51:07	the it of the group is a guy named steve krachewski and uh nier is a part of that team and uh
51:13	um a compelling advocate he's he's very excited about it and does a great job of
51:19	explaining why it's worth doing and i agree with them i think it's a will be a very informative study you mentioned
51:24	matt chamberlain so certainly you're aware of the work that matt and dan promislaw and their colleagues are doing
51:30	on dogs they're starting with rapamycin and i think that is also likely to be very informative and to give
51:37	more interesting more informative results in the span of about five years so
51:43	if they do find five or seven years from now that a drug like rapamycin
51:49	is extending the average lifespan of dogs by a year or two and keeping them not just alive but
51:56	relatively healthy with a good sense of smell and good good activity and good cardiovascular function good hearing
52:03	think that would be compelling evidence to suggest that that drug might be
52:09	beneficial for people the fda won't want to prove that but if you've
52:14	got evidence that a drug extends lifespan in mice extends healthy lifespan and dogs
52:20	the idea that it could do so and people becomes compelling and then it's a matter of
52:25	why is our medical establishment our legal establishment not able to work with that
52:31	yeah i'm i'm very excited about mike cabellon's work and on dogs so curious to stay updated on that

Curcumin, Green Tea Extract, MCT Oil

52:37	um so some of the other natural ones for example curcumin you know you hear all
52:42	the time oh it's so good for you um and similarly green green tea extract you tested both of
52:49	those as well did you see any health benefits of lifespan benefits
52:57	yeah when somebody says it's good for you you should ask them with a critical eye what evidence do you have
53:04	that is sometimes they'll say see put it on cells and the cells live or whatever marker you've got for so-called
53:10	senescence see that goes away or something and the relationship of that to whether you actually feel healthy and live
53:16	longer and disease-free is obscure to non-existent so whenever somebody says
53:23	i've got the very best curcumin on the market i will really improve your feelings of youthfulness
53:29	you really want to ask show me the data and show me the method
53:34	otherwise you're falling for a con artist basically uh curcumin we tested in the itp at one
53:41	dose had no effect uh green tea extract is once
53:47	one tiny bit more complicated there's a standard test we use it's called the log rank test
53:53	and using that test the green tea extract did not have any benefit in males or females
53:58	however when you look at the curve there is a hint in females only that the
54:05	very earliest deaths may have been the overall lifespan was not increased the median
54:10	was not increased the last 10 were not increased but the early deaths were slightly slower significantly
54:18	slower um so that's that's the sort of the asterisk
54:24	that goes next to green tea extract it could potentially have a female specific benefit if you if you narrow your focus
54:31	to the earliest deaths we're not going to chase that one down okay
54:37	mct mctl that's taken a lot of spotlight i think recently because of ketogenic
54:42	diets or what have you what did you observe with mct oil oh medium chain triglycerides yeah that
54:48	didn't work either well we're testing but it didn't work and we were given a drug called physin

Fisetin & Senolytics

54:54	which allegedly is a cenolitic allegedly right grooves senescent cells uh we
55:01	tried that at two different dose regimes it also had no benefit but
55:06	then that the mice we gave it to they also didn't have any deletion of semi-assassin cells so
55:13	we were neither able to reproduce the reported health benefit nor the reported change in senescent cells have you
55:20	tested any of the other synalytic drugs like quercetin
55:26	no no okay so you tested only faceting didn't absorb any results
55:32	didn't think it was worth promising no benefit and no harm and no overall senescent cells if you
55:39	have a company and your company is peddling a so-called sinolytic drug
55:44	you sometimes are very hesitant to let another lab test it right because if other lab tests it and finds it doesn't
55:51	work that's not good for your company it's not good for your stock price it's not good for your ability
55:56	to sell the stuff so many companies that are trying to
56:02	sell bottles of an allegedly senalytic agent
56:07	have no interest in our testing so i'm just confused i guess there are

Why most published research findings are false

56:13	all these papers that get published that oh fiacetine improved this metric or quercetin or
56:19	you know green tea extract or i guess what are some of the other ones we discussed um
56:25	what i mean are they do you think these studies are not being conducted rigorously what is going on how does a
56:32	consumer even trust some of these papers coming out
56:38	yeah i think it's a complex situation there's a very famous paper by a
56:44	statistician named john ionitis and the title of the paper is called why most research my
56:51	most published research findings are false and his paper goes into great detail
56:57	as to the ways in which the literature can be filled up with
57:02	findings that appear on the surface to be convincing but are never replicated and
57:08	don't turn out to represent the biological ground truth
57:13	one of these is that scientists tend to publish things that are positive but not publish things that
57:19	are negative and it's also the case whether through self-deception deliberate fraud or
57:26	accident uh people who have a company trying to sell a drug tend to find that
57:31	it works really well for them in their laboratories in our molecular biology of aging
57:38	journal club here in michigan for fun we assigned the students two papers
57:43	uh one of them came from company a and they showed that drug a is terrific at
57:49	removing senescent cells and producing all sorts of health benefits and mice as a negative control they use drug b
57:56	the other paper which we teach on the same day comes from the people who own company b they sell drug b
58:03	in their paper drug b works great it removes senescent cells and all sorts of health benefits they use drug a as their
58:10	negative control so my own rule of thumb i mean some of these
58:15	people may even have it right you never know but my rule of thumb is i don't believe
58:22	it until i see the work done over again by a group
58:27	that doesn't sell the stuff um that's one of the things about the itp
58:33	we take no intellectual property and we have no financial stake in any of these
58:38	drugs so if we find one that works that's thrilling we publish it we're really
58:43	pleased with ourselves the aging institute and the community research scientists is really pleased with
58:49	ourselves if it doesn't work we publish that anyway and that's one of the reasons why companies who
58:56	are trying to sell the drug are less enthusiastic about our working order with them
59:01	we won't accept a drug unless the sponsors of the drug the people who gave it to us
59:07	sign a statement saying we get to publish the results whether they are positive or negative
59:12	they cannot repress the publication of our results and every drug we ever study
59:19	we publish and for many companies they find that's not consistent with their commercial needs
59:24	yeah oh no i'm so glad talking to you to clarify some of these points there's just so much confusion all the papers
59:31	that comes out um something may be right i mean you know yeah it could well be that these drugs
59:37	actually work in people or in mice or in people and mice together yeah it's just
59:42	to cement the thing i want to see the stuff with good strong evidence for lifespan
59:48	and pathology in mice or well-defined health outcomes in people
59:54	and i want to see it confirmed preferably by people who are not trying to make money
1:00:00	from a company that is selling the drug right so at the itp are you testing any health

Healthspan biomarkers at the ITP

1:00:06	span biomarkers or is the focus mostly just on lifespan extension for example
1:00:11	yeah we have two phases um in the first phase lifespan is the only endpoint
1:00:18	because if we threw in a lot of other stuff like strength and balance and cognitive function and inflammatory
1:00:23	markers we could only test half as many drugs so those first stages we just want
1:00:29	to push through as many drugs as we can we have enough money to screen about seven each year
1:00:34	now if we have a winner uh we then do what we call a stage two study we put a lot of the mice on the
1:00:42	drugs some of them are euthanized for pathology some of them are used for physiological tests of health uh my lab
1:00:48	tests a lot of this biochemical stuff i've been telling you about randy strong's lab does a lot of pharmacology
1:00:54	they look at glucose tolerance something they're especially interested in david harrison and nadia rosenthal they're at
1:01:00	the jackson labs where they have lots of specialists in mouse behavioral testing and physiological
1:01:06	testing so they take some of the drug-treated mice all of these health outcomes tests
1:01:11	are um really important and we incorporate them into our second run with any of
1:01:17	the the drugs that work the other thing and it's sort of built into the philosophy of the program once we have a
1:01:23	drug that works we publish it and we're hoping that that is a stimulus so that the people who are
1:01:29	really good at studying mouse hearing will study hearing and drug-treated mice the people who are really good at
1:01:36	studying um bone diseases and neuronal turnover and cataracts and the
1:01:43	heart they will study with their special expertise mice
1:01:49	treated with some of these drugs the itp has collaborative programs for all of these i mean every drug we test we put
1:01:56	aside um tissues 11 tissues from 45 mice for each
1:02:02	drug so if a heart lab says can i please about the hearts from the mice treated
1:02:07	with this drug this drug and this drug we say yes and we ship it out the next week so we are setting ourselves up
1:02:14	for providing assistance and collaborative uh help to any lab with sufficient
1:02:21	expertise that wants frozen tissues from these drug-treated mice if the tests can only be done on live mice like a test of
1:02:29	memory uh we can assist them by providing them with the drug-treated food or very small
1:02:35	numbers of drug-treated mice okay so it is possible that some of the drugs that were tested in phase one

Can you have healthspan without lifespan?

1:02:42	could have health span benefits but did not have lifespan benefits are you asking whether any of the drugs
1:02:47	in our phase one studies might have improved lots of things but the mice then just dropped dead
1:02:53	yeah if they had if they had health span benefits like the myosphere went older and yeah that's a very
1:02:59	popular idea exactly it's a very popular idea and it's a shame um the people who used to run up until recently the
1:03:06	division of aging biology were fascinated by this notion that health spain and lifespan were really really
1:03:12	different and they sort of saw them as a seesaw they were interested in healthspan and
1:03:19	the implication was therefore you're not interested in lifespan you're interested in one or the other and healthspan was
1:03:26	the flavor of the decade but that's the very bad way to think about it the reason that our mice live so long is
1:03:31	they stay healthy for a long time it's not that they're on a see-saw they both go up together
1:03:38	so although it's possible in theory you could have a drug that makes you strong
1:03:44	and fit with great cognition and no cataracts an excellent hearing but you happen to be dead
1:03:51	it's not impossible but there's no evidence for anything of that sort happening that doesn't happen in caloric
1:03:57	restriction it doesn't happen in snail dwarf or gercomice or mystery with a carbos or 17 alpha estradiol or
1:04:03	rapamylasia or in fact anything i know about so our we use lifespan as a screen
1:04:11	and i guess it's possible in theory that we might be missing a drug that makes the animals healthy on multiple
1:04:17	dimensions without actually improving their mortality risk
1:04:24	it's not too hard to imagine this i mean if um let's say you're really interested in muscle aging if you made the mice do
1:04:30	push-ups every morning by gosh you would slow down the effects of aging on muscles you would slow down
1:04:37	cyclopedia you can imagine a tissue specific booster for one aspect of age sensitive
1:04:44	physiological function and i wouldn't be that interested in it uh
1:04:49	i'm interested principally in things that slow them all together
1:04:55	slow aging not just of the muscles but of the bones and the brain and the eyes and everything else
1:05:01	and anti-cancer defenses most particularly so
1:05:06	for my money the best time to actually do the studies of all of those important elements of health those
1:05:13	health outcomes is when you have a drug that you already know works in the sense of that postpones
1:05:19	lethal illnesses and all the ones we've ever looked at not only do they postpone legal illnesses they also postpone stuff
1:05:26	that is age sensitive but not lethal as we would guess as we would have voted
1:05:31	yeah i think you might be right i mean i would think that health span goes coincides with lifespan and now i'm even
1:05:37	beginning to wonder if you know when people say oh the health plan benefits but there may not be lifespan benefits
1:05:43	if that just ends up being a cover-up for some sort of study they're trying to push i don't
1:05:48	know i think it's a fundamental i think it's mostly political
1:05:54	if you are the president of the united states and this includes presidents i'm fond of the presidents of west florida
1:06:00	and you say we will cure cancer your approval goes up everybody wants to cure cancer
1:06:06	but if that same president instead goes on tv and says we're going to slow aging and all the diseases of aging
1:06:12	he or someday she is considered crazy really you're going to slow aging don't
1:06:17	be silly no one gets a slow aging and that's that's a matter of the political climate where where the
1:06:25	overton window is what people consider sensible scientific projection now i
1:06:30	don't think we're going to cure cancer i don't think we're anywhere near having a pill or a procedure that will postpone
1:06:38	lymphoma and colon cancer and breast cancer and brain cancer etc etc
1:06:44	in mysore people but we do have one thing that does that all of these anti-aging drugs do that
1:06:51	we can indeed slow cancer and as a side effect we slow hearing loss and we slow cataracts and we slow the loss of
1:06:58	cognition etc so to my point of view things that slow aging are eminently
1:07:04	feasible we have proof of principle now for at least four of them plus two unpublished in mice
1:07:12	and that's the way to go if you really seriously want to postpone alzheimer's and cancer at the same time and all the
1:07:18	other bad stuff you really want to have something that slows aging and we've got things that
1:07:24	actually do that fortunately it's not just science fiction anymore couldn't agree more um there are a
1:07:31	couple of last longevity drugs that i wanted to discuss with you one was fish oil
1:07:36	were there any benefits with fish oil no i mean you know you've read or published papers we tested it at two

Fish Oil, Spermidine, Sulforophane

1:07:42	concentrations it had no health benefits it might have worked at a different concentration it might have worked on a
1:07:47	different diet it might work in people you never know but it certainly didn't work mice
1:07:53	okay and spermadine and sulforaphane is that part of the ongoing cohort has that
1:07:58	been tested already no each of them post poses its own difficulties sulfurophane which is an
1:08:05	inducer of the stress pathways related to nerve makes a lot of sense unfortunately it's
1:08:12	exceptionally unstable people in my left spend a year trying to get sulforaphane into mouse food of any sort so that
1:08:19	there was enough of it still left that it would boost nerve two in the mice and we failed
1:08:25	we could never get enough active sulfurophane into the mice to have any pharmacological effect so i like the
1:08:32	idea but it didn't work out we did a collaboration twice now with a group that had
1:08:40	botanical agents that they thought would lead to nerf to activation just as
1:08:46	sulfurophane does we tested both of them one of them did have a small but significant
1:08:54	increase in male mouse lifespan the maximum lifespan was not increased but the average did go up
1:09:00	and then we tested another product from the same group which they said was stronger and that had no benefit at all in either
1:09:07	sex so i still think it's a good idea the idea of doing something like sulfuric vein
1:09:13	but we haven't yet come across something you can stick in the food that actually
1:09:19	produces a strong benefit do you think it's the same for humans where it's maybe just not absorbed as
1:09:25	well i i don't know um there's a company
1:09:31	that is selling extracts of broccoli they wanted us to test it but they wanted us
1:09:38	to put mice on a diet that was 20 broccoli and we decided not to do that
1:09:45	the other drug you mentioned was spermatine a very fine
1:09:50	uh scientist frank podeo recommended that we try this told us how much to use and whenever
1:09:55	before we start a lifespan experiment we always give the mice the drug for eight weeks just to see if it gets in and we
1:10:02	put them on spermadine and eight weeks later we found no increase in spermidine in the blood or the liver or any of the
1:10:09	other tissues now spermadine starts at a non-zero level mice make it all the time so it's
1:10:15	always there so we were comparing the normal level which is quite substantial to the augmented level which was the
1:10:21	same as the normal level so they said oh oh yeah i forgot to mention it takes six months
1:10:26	before it starts to increase we said sure so we gave it to mice for
1:10:32	six months and then tested it in serum liver brain and all the other tissues and we saw no increase it had no effects
1:10:38	so we were not willing to test a drug in mice unless we could prove
1:10:44	that it was changing their intrinsic level of spermite in at least one tissue and
1:10:49	there were no effects no signs that adding the stuff to the diet modified sperming or spermidine levels
1:10:56	in any of the tissues of our mice so we gave up i see so do you know
1:11:02	the the scientists who maybe did work on spermadine uh were they giving it in a
1:11:07	different way to mice or maybe they were just looking at the intrinsic permitting levels
1:11:13	we used the amount they told us to use in the form they told us to use it and
1:11:19	when it was time to measure the amount in the tissues we gave them the tissues blinded so they could use their methods
1:11:25	to measure spermine and spermidine and then when they sent us the data we gave them the code and it was at that point
1:11:31	that we and they simultaneously concluded there was no effect of putting the stuff in the diet on either spermine
1:11:38	or spermidine levels in any of the tissues whether we looked at eight weeks or six months
1:11:44	i see oh all right well um lastly what i i heard brian kennedy
1:11:50	on an earlier version of your podcast saying he was really down on uh really
1:11:55	good in on spermany and swimming he was going to try that in some humans and i respect brian and i would certainly love
1:12:02	to hear what evidence he has that the stuff has any effect maybe he has evidence uh i would like to
1:12:08	hear what it is fantastic are there any other supplements or drugs that maybe you're

Unpublished data Richard is excited about

1:12:14	excited about um that i haven't brought up haven't discussed yeah we the we have unpublished data
1:12:21	that i'm allowed to mention but we are not ready to publish it yet and i'm only allowed to mention it if i
1:12:28	include the statement that it's preliminary that we have a lot of mice that have died yet so the data are going to change
1:12:34	and that we have no mice dying yet at very old ages so all of the data comes from mice that are
1:12:41	either young adults or middle-aged but both findings are really quite interesting because they're over-the-counter preparations
1:12:48	one of them is a product called astaxanthin you can buy it at your local plum market or cvs store or other uh
1:12:55	store specializing in so-called health products um and the other of these is even better
1:13:01	known it's called mechlazine the trade name for my cuisine is uh dramamine or antivert or a bonin i've actually taken
1:13:08	that once i went on a trip to antarctica it's an anti-sea sickness drug it helps you not get nauseous if you're on
1:13:14	milwaukee seas so both of these drugs or health supplements or whatever you
1:13:20	want to call them are available over the counter without a prescription for that reason someone has decided that
1:13:26	they're not harmful which is always a great thing the preliminary data so far suggests
1:13:33	that both of them are going to be once all the data are in will have um significant benefits in males
1:13:40	and we don't know yet about females because the females are a little longer lived it takes a few more months to get
1:13:46	enough deaths in the female population to really be able to assess individual
1:13:52	compounds so we don't know yet about females but both drugs so far look pretty good for males about a year from
1:13:58	now when 90 or more of the mice are dead we'll do the official analysis
1:14:04	hopefully it will come out the same way we'll publish the paper and um that will be really nice because it'll
1:14:11	give two new tools whose mechanism of action can be explored we can evaluate them
1:14:16	for the sort of cellular changes i mentioned to you earlier in our discussion but also because um
1:14:25	if you're like matt cameron and then promise low and you're interested in products you could give to
1:14:30	healthy adult dogs that are not going to hurt them and could potentially improve their healthy
1:14:37	lifespan these would be perfectly decent candidates if it turns out they're sex
1:14:43	specific that also will give us new tools for trying to figure out why some of these drugs work only in
1:14:49	males and some work in both sexes so the first one you mentioned what is
1:14:54	it commonly taken for by people right now um
1:15:00	i don't know it's a health some it's a health supplement the claims made there are ten
1:15:06	companies that make the stuff um it's actually
1:15:11	uh legal to use it in people as a food coloring agent um
1:15:16	so it's it's being used for why look it up uh online use wikipedia for astaxanthin get a long
1:15:23	list of industrial uses of the stuff and um whether it is actually
1:15:28	producing specific health benefits of people is not an area where i'm i'm competent to comment
1:15:35	yeah yeah yeah and do you have any insights yet on the mechanisms by which either of these two might be working
1:15:44	well no um the problem for any one drug is they usually do too many things right so
1:15:52	um if a given drug you know let's let's take uh dramamine or antibiotic or
1:15:59	um mechazine it's it's known to make it more difficult to feel nausea and it's an
1:16:05	anti-vomiting agent uh and the pathways in the brain
1:16:11	that it activates to do that are ones involving famous neurotransmitters that
1:16:16	modify you know your feelings of good health and how these are changed by
1:16:21	seasickness but that doesn't prove that those are also involved in lifespan the drug could affect 10 different target
1:16:28	enzymes 20 different target enzymes some of which are related to nausea some of which are related to metabolic processes
1:16:36	or cancer processes relevant to aging only when we've got if we have
1:16:42	eventually strong data that it has a an anti-aging effect will it be
1:16:49	worth the effort to figure out how it's actually working there it came to our attention because of a
1:16:55	collaborating scientist a man named gino corto posse gino knew that rapamycin was
1:17:01	an inhibitor of tor and he did the study of thousands of drugs
1:17:07	uh to say which of these are good at inhibiting tor and especially he limited himself to fda
1:17:13	approved drugs plus he wanted stuff that wouldn't hurt people and necrozine came out very very well
1:17:21	as a torah inhibitor i thought that was a good reason to test it now we don't know if it has a benefit
1:17:27	we don't know whether that benefit is going to be attributable to tor inhibition or some other mechanism or multiple
1:17:33	mechanisms but that was the mechanism that gino thought
1:17:39	raised this to the level that it deserved an expensive five-year lifespan study
1:17:46	amazing yeah one last thing i want to say i mean i read some of your writing pieces um the one on flying pigs and

Flying Pigs & Aubrey De Grey

1:17:53	also the arbitrator in old wise i think was just was fantastic you have a great
1:17:59	sense of humor and a writing style yeah thank you
1:18:04	the first time we had a mouse that was about to get to be four years of age i i was associated at a time with
1:18:11	a website that science magazine had set up for biology of aging and i asked them would they allow me to publish the
1:18:18	birthday announcement of the mouse when it made it to four years of age and they said sure sure do that
1:18:24	and unfortunately the mouse died 11 days prior to its fourth birthday
1:18:30	uh so then let me publish the obituary on the website and it's also on my my labs website at this point
1:18:37	the flying pigs article pertains to claims made by aubry de grey
1:18:42	that he and he alone can save it uh he has an idea that if you simply follow
1:18:48	the seven biochemical pathways that he has written down you can stop aging in
1:18:54	his tracks and people can live more or less forever i thought this was silly and so i wrote a parody
1:19:00	of uh dr de gray's arguments as to ways in which seven
1:19:06	specific interventions could be used to turn pigs into flying pigs and that that was published in the mit alumni magazine
1:19:13	which had just recently published a seven page article explaining how how thrilling it was that dr gray's ideas
1:19:20	had made it possible to stop the aging process or we would soon be doing so i i thought it was time for
1:19:27	another point of view both of these are um available you can download them from my
1:19:33	website if you want to uh if you're interested in this that sort of stuff but i'll link
1:19:38	to it i thought it was very clever um good is there anything else that
1:19:43	maybe i haven't asked you or you want to touch upon any last words no no i'm glad for the opportunity to
1:19:50	chat with you i the number of invitations people get to talk
1:19:56	to sensible scientists about the biology of aging is at what i hope will be the

Exponential rise in aging research

1:20:01	very beginnings of an exponential rise it's certainly a lot more this year than there were three or four years ago i think it's a sign generally that
1:20:09	people are beginning to understand the potential for human health and disease prevention
1:20:15	of strong anti-aging research and also gradually beginning to
1:20:21	filter out the the snake oil salesman and those who are making ex
1:20:27	extravagant claims to make some money from the good science and recognizing that there is a good after you clear all
1:20:33	the junk away there really is a core of exciting science that's coming along i'm
1:20:38	i'm really pleased to see that it's taken too long but at least to see it happening now and so i'm delighted to
1:20:44	participate in a show like this that has that as its central focus exactly i do hope to uncover that for
1:20:51	people and give people this helpful information so thank you so much for your time today it's been absolutely
1:20:56	wonderful learned so much hey everyone i hope you enjoyed the episode
1:21:01	i'm blown away by the pace of longevity research and i want to keep bringing you great conversations with longevity
1:21:09	scientists themselves if you want to support the creation of the podcast consider sharing it leaving
1:21:16	a review on apple podcast or signing up to be a premium member for show notes
1:21:21	all resources can be found at livelongerworld.com
1:21:26	as you all know aging is universal we can unite in this fight and be
1:21:32	healthy forever i can't wait and see you next time
1:21:39	[Music]