Can We Reverse Aging? The Anti-Aging Secrets of Epigenetics

Jul 13, 2023 | Written by Anurag Srivastava, PhD | Reviewed by Scott Sherr, MD and Marion Hall

Can We Reverse Aging? The Anti-Aging Secrets of Epigenetics

Starting from the very beginning of our existence, the process of aging initiates. It involves the deterioration of cellular structures, gene regulation, and DNA sequences, leading to the aging of individual cells and entire organisms. It is estimated that by 2050, the number of people aged over 80 will triple globally [1]. Earlier findings have pointed out that aging is mainly caused by the loss of genetic information caused by mutations due to DNA damage. However, questions have been raised regarding the dominant role of genetic information loss in driving the aging process [2-5].

Studies have suggested that aging could be caused by a loss of epigenetic information rather than genetic information. Longevity researchers are trying to understand the root cause of aging and probing whether it is possible to reverse it. They have equated the process of aging to a software problem, wherein it arises from corrupted epigenetic information [6]. As such, aging could be reversed using a pre-existing backup copy of epigenetic information [5-7].

Take a look at this previous article for an overview on epigenetics before reading further!

Aging hypotheses

There are numerous hypotheses proposed to get a better understanding of the aging process. Some of them are as follows:

  1. Free radical theory of aging: It proposes that cell and tissue aging are a result of free radical attacks [8].
  2. Relocalization of chromatin modifiers (RCM) hypothesis: The RCM hypothesis states that epigenetic changes due to the relocalization of chromatin factors in response to DNA damage may be the chief cause of aging [2-4].
  3. The mitochondrial theory of aging: As we grow older, mitochondria gradually accumulate damage caused by reactive oxygen species (ROS) and begin to lose their functionality [9]. Over time, this decline in cellular function contributes to aging and eventually leads to cell death.
  4. Information theory of aging (ITA): ITA proposes that aging in eukaryotes is due to the loss of transcriptional networks and epigenetic information over time, driven by a conserved mechanism that evolved to co-regulate responses to cellular damage [2,3,7].

Epigenetic changes are the main factors behind aging

David Sinclair’s lab developed a model that would induce double-stranded breaks (DSBs) in cells and mice when exposed to tamoxifen (TAM) without causing mutations [7,10]. They called this model inducible change to the epigenome (ICE) system [10]. They used the ICE system to test that mammalian aging is caused by epigenetic changes in cells and mice. The authors found that ICE-treated cells and mice were older than that of their controls.

The key hallmarks of aging in the ICE-treated cells and mice were as follows [7]:

Hallmarks of aging in ICE-treated cells [7]

  1. 1.5-fold older than control cells
  2. More susceptible to DNA-damaging agents
  3. Increased indication of cellular senescence with a reduction in lamin B1
  4. Accelerated epigenetic clock

Hallmarks of aging in one-month-old ICE-treated mice [7,10]

  1. Increased alopecia
  2. Increased loss of pigments on the feet, tail, ears, and nose resembling a middle-aged control mouse
  3. Lower respiratory exchange ratio
  4. Decreased motion
  5. Increased body weight loss

Hallmarks of aging in ten-month-old ICE-treated mice [7,10]

  1. Histological changes in the kidney (fewer healthy glomeruli)
  2. Changes in skin (subepidermal thinning and hair graying)
  3. Slowing of the central nervous system
  4. Loss of memory
  5. Increased activity of astrocytes and microglia
  6. Lessen muscle mass
  7. Reduced endurance
  8. High levels of lactate post-exercise
  9. Reduced mitochondrial functions
  10. The epigenetic aging rate (DNA methylation clock) was 50% faster than the control mice model
  11. Accelerated age-related changes to chromatin, gene expression, and loss of cellular identity

The study also found that ICE treatment in mice corrupted the epigenetic information with lower amounts of H3K27ac and H3K56ac and higher amounts of H3K122ac, which are hallmarks of rapid aging [7].

Can aging be reversed?

Expression of Yamanaka Factors in ICE-treated mice and cells led to the reversal of aging by 57% [7]. The five-week exposure to Yamanaka Factors led to the rejuvenation of aging markers in kidneys, skin, and muscles to a point that they resembled negative controls [7,10]. Another study showed that it was possible to rescue aged phenotypes in mouse retinal ganglion through DNA demethylation [5].

Intervention for delaying and resetting aging

With proof in hand, it is clear that aging can be delayed and reset if proper interventions are employed. In a recent interview, David Sinclair said, “My calculated biological age has been going down for the past decade or more to a point where I am predicted to live at least a decade longer than I would have if I hadn't done anything. So it's never too late to start changing lifestyle choices.

Longevity research has given us many interventions to delay our aging process. The key modulators for longevity are as follows:

Methylene Blue

Methylene Blue (MB) is known to activate mitochondrial function and is obviously one of our favorite compounds. To get an in-depth understanding of MB, you can read MB dosing to optimize health, MB the color of neuroprotection, MAOI-MB connection, and all you need to know about MB. As per the free radical and mitochondrial theories of aging, mitochondria play a vital role in aging [8,9]. To regulate or delay the aging process, MB comes in pretty handy. Low-dose treatment of MB is found to delay brain aging and may protect against Alzheimer’s Disease [11].

Studies have found that MB protects skin from oxidative stress and delays aging [12]. Another study in the fibroblast found that MB treatment could increase lifespan and cell proliferation while reducing aging markers [13]. MB-treated skin cells exhibited superior performance to the other cells, displaying significant capabilities in promoting cell proliferation and reducing markers associated with aging [13,14]. MB treatment in human keratinocytes offers extensive absorption of UV rays across different wavelengths. It effectively reduces the occurrence of DNA DSBs caused by UVB irradiation, hence reducing the chance of aging caused by loss of epigenetic information [7,13,14].

Reducing Stress

A recent study from Yale showed that stress increases biological and epigenetic aging, and reducing stress has a positive effect on delaying aging [15]. A meta-analysis found a correlation between stress and epigenetic aging [16]. These results suggest that reducing stress could be beneficial in delaying the aging process. Many stress-reducing techniques exist, such as yoga, meditation, breathing techniques, and keeping the jerks away (yes, we said jerks). To learn more about the top ten techniques to reduce stress, read here and here. Additionally, you can use Tro Calm to de-stress.

Intermittent Fasting (IF)

Intermittent fasting (IF) induces changes in the body that promote healthy cells and DNA, consequently slowing down the aging process [17]. A rat study observed that aging was delayed by up to 80% when the rats were maintained on IF diets starting from five weeks of age [18]. The Madeo group reported that a six-month treatment of IF diets in the middle-aged human group improved the parameters associated with cardiovascular diseases and metabolic disorders. Additionally, they found that the hallmarks of aging were decreased [19].

To fully harness the longevity benefits, it is crucial to understand the specific fasting protocols, their durations, and the underlying mechanisms that can optimize the desired effects [17]. It is also important to recognize and address any potential negative impacts that may offset positive outcomes.

Vitamin D

Vitamin D is a steroid hormone and micronutrient in many biological pathways and functions. To learn more about vitamin D, read here. Vitamin D supplementation increases telomerase activity, hence becoming an anti-aging agent. A recent clinical trial with vitamin D supplementation in obese African-Americans found that it decreased the DNA methylation clock by 1.85 years [20]. Another clinical trial found a reduction in the biological age of 1.47 years after one year of a Mediterranean diet plus 400IU vitamin D3 [21].


Resveratrol is a polyphenol and an important constituent of the epigenetic diet [22]. Longevity research has found that resveratrol is an important anti-aging agent. A meta-analysis of 19 published papers involving six species revealed that resveratrol exhibited life-extending properties [23]. Another study found that resveratrol supplementation extended the lifespan of flies in a dose-dependent manner [24]. This effect was achieved by reducing ROS and providing neuroprotection [24,25]. Resveratrol has been shown to lower the risk of diseases associated with aging, like neurodegenerative disorders, cancer, cardiovascular disease, and infertility [25].

Nicotinamide (NAD) supplements

The seminal work of Eduardo Chini showed the CD38 pathway as the main regulator of intracellular NAD+ levels and sirtuin 1 activity in living organisms [26]. His group showed that a decline in NAD+ is associated with accelerated aging, and NAD supplementation slows it [27,28].


Studies have found that sitting for more than eight hours regularly is as deadly as smoking, as it affects not only vital functions but also accelerates biological aging [29,30]. Hence, doing exercise regularly decreases the chances of oxidative stress-related disease, aging, and improves health [31]. Exercise energizes the mitochondria and thus reduces ROS generation [31]. Exercise also helps in reducing the DNA methylation levels of genes, which is beneficial for de-accelerating the epigenetic clock [32].


With the advancement of longevity research, it is clear that the loss of epigenetic information is the root cause of aging. Further studies are required to understand the crosstalk between loss of epigenetic information and mitochondrial decline in aging. It has become clear with the recent work of Sinclair's lab that it is possible to reset and delay aging, and that mammals have a backup copy of their youth epigenetic information that can be used to reverse it. It's only a matter of time that scientists begin reversing the age of our organs, or brains, and more. Are you ready to be reversed?! 

For more information on the clinical applications of epigenetics, go to



  1. Fontana, L., Kennedy, B. K., Longo, V. D., Seals, D. & Melov, S. Medical research: treat ageing. Nature 511, 405–407 (2014).

  2. Kane, A. E. & Sinclair, D. A. Epigenetic changes during aging and their reprogramming potential. Crit Rev Biochem Mol Biol 54, 61–83 (2019).

  3. Oberdoerffer, P. & Sinclair, D. A. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol 8, 692–702 (2007).

  4. Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell 91, 1033–1042 (1997).

  5. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020).

  6. Sinclair, D. A. & LaPlante, M. D. Lifespan: Why we age—And why we Don’t have to. (Atria books, 2019).

  7. Yang, J.-H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell (2023).

  8. Harraan, D. Aging: a theory based on free radical and radiation chemistry. (1955).

  9. Chistiakov, D. A., Sobenin, I. A., Revin, V. V, Orekhov, A. N. & Bobryshev, Y. V. Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014, (2014).

  10. Teefy, B. B. & Benayoun, B. A. Putting aging on ICE. Cell Metab 35, 383–385 (2023).

  11. Poteet, E. et al. Neuroprotective actions of methylene blue and its derivatives. PLoS One 7, e48279 (2012).

  12. Atamna, H. et al. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. The FASEB Journal 22, 703–712 (2008).

  13. Xiong, Z.-M. et al. Anti-aging potentials of methylene blue for human skin longevity. Sci Rep 7, 2475 (2017).

  14. Xue, H., Thaivalappil, A. & Cao, K. The potentials of methylene blue as an anti-aging drug. Cells 10, 3379 (2021).

  15. Harvanek, Z. M., Fogelman, N., Xu, K. & Sinha, R. Psychological and biological resilience modulates the effects of stress on epigenetic aging. Transl Psychiatry 11, 601 (2021).

  16. Protsenko, E., Wolkowitz, O. M. & Yaffe, K. Associations of stress and stress-related psychiatric disorders with GrimAge acceleration: review and suggestions for future work. Transl Psychiatry 13, 142 (2023).

  17. Longo, V. D., Di Tano, M., Mattson, M. P. & Guidi, N. Intermittent and periodic fasting, longevity and disease. Nat Aging 1, 47–59 (2021).

  18. Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R. & Cider, N. L. Effects of intermittent feeding upon growth and life span in rats. Gerontology 28, 233–241 (1982).

  19. Stekovic, S. et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab 30, 462–476 (2019).

  20. Chen, L. et al. Effects of vitamin D3 supplementation on epigenetic aging in overweight and obese African Americans with suboptimal vitamin D status: a randomized clinical trial. The Journals of Gerontology: Series A 74, 91–98 (2019).

  21. Gensous, N. et al. One-year Mediterranean diet promotes epigenetic rejuvenation with country-and sex-specific effects: a pilot study from the NU-AGE project. Geroscience 42, 687–701 (2020).

  22. Hardy, T. M. & Tollefsbol, T. O. Epigenetic diet: impact on the epigenome and cancer. Epigenomics 3, 503–518 (2011).

  23. Hector, K. L., Lagisz, M. & Nakagawa, S. The effect of resveratrol on longevity across species: a meta-analysis. Biol Lett 8, 790–793 (2012).

  24. Chandrashekara, K. T. & Shakarad, M. N. Aloe vera or resveratrol supplementation in larval diet delays adult aging in the fruit fly, Drosophila melanogaster. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 66, 965–971 (2011).

  25. Zhou, D.-D. et al. Effects and mechanisms of resveratrol on aging and age-related diseases. Oxid Med Cell Longev 2021, 1–15 (2021).

  26. Escande, C. et al. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62, 1084–1093 (2013).

  27. Hogan, K. A., Chini, C. C. S. & Chini, E. N. The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging, and metabolic diseases. Front Immunol 10, 1187 (2019).

  28. Chini, C. C. S., Zeidler, J. D., Kashyap, S., Warner, G. & Chini, E. N. Evolving concepts in NAD+ metabolism. Cell Metab 33, 1076–1087 (2021).

  29. Beck, A. M. & Eyler, A. Is sitting really the new smoking? Am J Public Health 109, e11 (2019).

  30. Baddeley, B., Sornalingam, S. & Cooper, M. Sitting is the new smoking: where do we stand? British Journal of General Practice 66, 258 (2016).

  31. Rea, I. M. Towards ageing well: Use it or lose it: Exercise, epigenetics and cognition. Biogerontology 18, 679–691 (2017).

  32. Światowy, W. J. et al. Physical activity and DNA methylation in humans. Int J Mol Sci 22, 12989 (2021).

Comments (0)

There are no comments for this article. Be the first one to leave a message!

Leave a comment

Please note: comments must be approved before they are published

AI-generated responses are for informational purposes only and do not constitute medical advice. Accuracy, completeness, or timeliness are not guaranteed. Use at your own risk.

Trixie - AI assistant