Caloric Restriction May Unlock Epigenetic Secrets to Longevity

“To lengthen thy life, lessen thy meals.” – Benjamin Franklin.

For millennia, fasting has been lauded as a path to discipline, purity, longevity, and mental acuity. While Franklin may not have always heeded his own advice, his contention, one shared by many cultures throughout history, is now backed by over eight decades of scientific research.

Caloric restriction (CR) is the most thoroughly studied longevity intervention to date. In humans and animals, it consistently increases lifespan and healthspan (McDonald, 2010).

Any CR strategy may have drawbacks; for some, the good it may do is outweighed by unwanted side effects. Those with digestive issues or trouble regulating their glucose levels, for instance.

Some day, epigenetically informed medicine could deliver the benefits of caloric restriction without the discomfort of deprivation.

Why Does it Work?

The hallmarks of aging are a touchstone of biogerontology. Nine were originally identified, and more have been added since (Lopez et al., 2023). As the underpinnings of the aging process, taming them could let us delay, prevent, or even reverse everything from cancer to Alzheimer’s.

Epigenetic mechanisms play a pivotal part in all of the hallmarks. In fact, epigenetic drift, as covered in a previous WIE piece on caloric restriction, is itself a hallmark (Kirkpatrick, 2017).

This drift is slower in humans than monkeys and slower in monkeys than rodents. For all these species, drift is slowed by CR (Maegawa, 2017).

Caloric restriction typically involves a 20-50% decrease in daily caloric intake, provided that the individual receives all their essential nutrients (Colmon, 2009). However, this can be hard to do in practice.

Not only are extended lifespans observed, but positive outcomes for healthspan too: this includes a drop in issues like diabetes, neurodegenerative conditions, cardiac events, and various cancers (Gensous, 2019).

CR’s Epigenetic Mechanisms

Epigenetics refers to changes in gene expression. These changes never stop taking place.
Because epigenetic mechanisms are the interpreters of our DNA, it is not surprising that they exert tremendous influence in driving it forward and, if we learn how to manage them, backward as well (Kumar, 2016).

Two forms of epigenetic change, particularly DNA methylation and histone modification, have an abundance of evidence pointing to their therapeutic potential for managing the unpleasant aspects of getting older (Zhai, 2023).

DNA Methylation

Due to aging’s toll on gene expression, chromatin integrity and homeostasis are reduced. Genomic instability, another hallmark of aging, facilitates the mutations that can lead to cancer (Yao, 2014).
Aging precipitates severe disturbances in the distribution of 5-methylcytosine (the product of DNA methylation). This diminution leads to a genome-wide reduction in DNA methylation.

As this takes place, specific regions are methylated, silencing genes and potentially promoting tumor-causing genes, as well as other aging-related genes, like TIG1 and RUNX3, to activate (Li, 2011).

DNA Methylation in CR

Genomic regions prone to differential methylation with age are less altered in CR animals (Sziráki, 2018).
Eight separate studies have reported that CR is a buffer against age-related DNA methylation augmentations in different mammalian tissues: blood, liver, hippocampus, kidney, and cerebellum (Gensous, 2019).

The refashioned patterns of DNA methylation linked with CR can affect areas associated with degenerative illnesses. CR attenuates age-related methylation changes in promoters associated with cancer, diabetes, and inflammation in the kidneys of elderly rats (Kim, 2016).

Research on obese subjects shows that even short-term CR intervention results in epigenetic changes through DNA methylation of the WT1, ATP10A, and TNF-a genes, reducing gene expression of lipid metabolism. This appears to delay the aging process (Hahn, 2017).

Histone Modification in CR

Histones are proteins found in chromatin that form nucleosome structures with DNA. Chromatin is not a static structure but a dynamic and highly responsive scaffold (Bannister, 2011).

CR seems to modulate aging partially through changes to histone methylation. During CR, chromosome conformation changes, hTERT (human telomerase) is activated, and the H3K4 locus is trimethylated.
These conditions caused by glucose restriction inhibit cellular senescence and foster a significant extension in cellular lifespans (Li. 2011).

This was found to occur through the reduction of p16 cells under glucose deprivation. The induction of chromatin reconstitution through effects on promoter methylation extended cell life (Li. 2011).

CR slows aging and protects against its associated maladies in part by upturning unwanted epigenetic changes. As new therapeutics are developed and more regions are elucidated upon, we may all soon reap the rewards of fasting—without the drawbacks.

References and Suggested Reading:

1. Bannister, A. and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Research, 21(2), 381-395.
2. Gensous, N., Franceschi, C., Santoro, A., Milazzo, M., Garagnani, P., and Bacalini, M.G. (2019). The Impact of Caloric Restriction on the Epigenetic Signatures of Aging. International Journal of Molecular Sciences, 20(8), 2022. doi: 10.3390/ijms20082022.
3. Hahn, O., Grönke, S., Stubbs, T. M., Ficz, G., Hendrich, O., Krueger, F. et al. (2017). Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biology, 18(1), 56. doi:10.1186/s13059-017-1154-8.
4. Kim, C.H., Lee, E.K., Choi, Y.J., An, H.J., Jeong, H.O., Park, D., Kim, B.C., Yu, B.P., Bhak, J., and Chung, H.Y. (2016). Short-term calorie restriction ameliorates genomewide, age-related alterations in DNA methylation. Aging Cell, 15, 1074–1081. doi: 10.1111/acel.12473.
5. Kumar, S. and Lombard, D. B. (2016). Finding ponce de leon’s pill: Challenges in screening for anti-aging molecules. F1000Research, 5, 7821. doi:10.12688/f1000research.7821.1.
6. Li, Y. and Tollefsbol, T. O. (2011). P16(Ink4a) suppression by glucose restriction contributes to human cellular lifespan extension through sirt1-mediated epigenetic and genetic mechanisms. PLoS One, 6(2), e17554. doi:10.1371/journal.pone.0017554.
7. Li, Y., Daniel, M. and Tollefsbol, T.O. (2011). Epigenetic regulation of caloric restriction in aging. BMC Medicine, 9, 98.
8. López-Otín, C. et al. (2023). Hallmarks of aging: An expanding universe. Cell, 86(2), 243-278.
9. McDonald, R.B. and Ramsey, J.J. (2010). Honoring Clive McCay and 75 years of calorie restriction research. Journal of Nutrition, 140(7), 1205-1210. doi: 10.3945/jn.110.124106.
10. Sziráki, A., Tyshkovskiy, A. and Gladyshev, V.N. (2018). Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell, 17, e12729. doi: 10.1111/acel.12729.
11. Zhai, J., Kongsberg, W.H., Pan, Y., Hao, C., Wang, X. and Sun, J. (2023). Caloric restriction induced epigenetic effects on aging. Frontiers in Cell and Developmental Biology, 10, 1093785. doi: