Caloric Restriction

Caloric restriction (CR), a dietary regimen that reduces calorie intake without incurring malnutrition, has been a subject of scientific study in the context of aging and longevity. This practice is thought to extend lifespan and improve health outcomes in various species, including potentially humans.

Science Behind Caloric Restriction

Mechanisms

Caloric restriction is believed to impact aging through several biological pathways. These include reduced metabolic rate, decreased oxidative stress, improved insulin sensitivity, and activation of cellular maintenance mechanisms such as autophagy.

Research Findings

Studies in model organisms, like yeast, worms, flies, and mice, have consistently shown lifespan extension with caloric restriction. Human studies, however, are more complex due to longer lifespans and ethical considerations.

Benefits of Caloric Restriction

Research suggests that caloric restriction may offer several health benefits, including:

Improved metabolic health
Reduced risk of age-related diseases
Enhanced brain function and protection against neurodegenerative diseases
Possible extension of healthy lifespan

Potential Risks and Concerns

Caloric restriction, especially if not properly managed, can lead to:

Nutritional deficiencies
Loss of bone density
Reduced muscle mass and strength
Psychological challenges such as food obsession and social isolation

Guidelines for Safe Practice

Before starting caloric restriction, it is crucial to consult healthcare professionals. Some general guidelines include:

Gradual reduction in calorie intake
Emphasis on nutrient-dense foods
Regular monitoring of health parameters
Adjustment of diet based on individual health needs and lifestyle

Conclusion

While caloric restriction shows promise as a tool for extending healthspan and potentially lifespan, further research, especially in humans, is necessary. It is vital to approach this dietary regimen with caution and under medical supervision to avoid adverse effects.

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In fact, it has been shown that caloric restriction increases NAD+ bioavailability by activating the expression of NAMPT (nicotinamide phosphoribosyltransferase, which transforms nicotinamide [NAM] to NAD+ in the NAD+ salvage pathway) ^[1]

References

↑ Menssen A et al.: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012. (PMID 22190494) [PubMed] [DOI] [Full text] Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.

[pmid22190494-1] Menssen A et al.: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. Proc Natl Acad Sci U S A 2012. (PMID 22190494) [PubMed] [DOI] [Full text] Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.

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