The Pathways of Aging: Repair and Recycling

In this installment of our five-part series on the pathways of aging, we explore the repair and recycling of cellular components and macromolecules. As organisms age, damage can gradually accumulate within cells, leading to various detrimental effects. However, nature has equipped certain species with remarkable mechanisms to combat this damage by efficiently removing accumulated cellular wear and tear through specific pathways.

Throughout this article, we will explore several key topics central to this process. First, we’ll examine the role of SIRTs, a group of proteins involved in regulating cellular health and longevity. Next, we’ll dive into Autophagy, a crucial process responsible for breaking down and recycling damaged cellular components, ensuring the cell’s overall well-being. Additionally, we will explore the intricate world of DNA repair and its significance in maintaining the integrity of genetic material. Lastly, we’ll shed light on the essential role of PARP and TFEB, two factors that play vital roles in the repair and recycling mechanisms of long-lived species.

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This is the third article in our five-part “The Pathways of Aging” series, where we introduce the most important pathways and concepts in aging research. Each article addresses a major category according to the underlying biology.

1. Growth Pathways and Nutrient Sensing
2. Resilience to Molecular Damage and Stress
3. Repair and Recycling
4. Rejuvenation of Cells, Tissues, and Stem Cells
5. Metabolic Health

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Table of Contents

• SIRTs
• Autophagy
• DNA repair and PARP
• TFEB

NAD+ and Sirtuins: A Powerful Duo for Enhancing Healthspan

In humans, seven proteins belong to a protein family called sirtuins. These are a class of proteins that usually work as deacetylases, which means they remove acetyl groups from other proteins in order to modulate their function. However, several sirtuins have also evolved to have other functions like DNA repair in the case of SIRT6.

SIRT1, specifically, became famous as the putative target of the pro-longevity molecule resveratrol. Later data, however, called this result into question (Brenner 2022), and SIRT6 emerged as the most promising sirtuin (Korotkov et al. 2021). Multiple studies found that overexpressing SIRT6 extends mouse lifespan, whereas neither SIRT1 nor resveratrol did (Roichman et al. 2021).

This is not to say that SIRT1 has no role to play in longevity, just not nearly as large of a contributor as once thought. Although it fails to extend lifespan by itself, at least one study suggested that it is necessary for caloric restriction to work in mice, and others found that SIRT1 is elevated in fat tissue of restricted mice (Mercken et al. 2014, Miller et al. 2017).

The molecule NAD is necessary for SIRT1 to deacetylate other proteins and, consistent with the above studies, it was found that NAD supplementation in mice improves health span (Mitchell et al. 2018). NMN, contained in NOVOS Boost, is a potent ingredient that is capable of raising NAD+ levels in humans

Autophagy: A Key Mechanism for Cellular Renewal and Longevity

The process of autophagy literally translates to self-eating. Our cells continuously degrade some of their internal “structures” through this process of self-eating. One theory of aging postulates that as we age, our cells and tissues accumulate damaged and misfolded proteins, and unsurprisingly, improved degradation and recycling of these proteins is beneficial. As proof of this principle, it was shown that mice overexpressing the autophagy gene Atg5 live longer (Pyo et al. 2013).

Autophagy is stimulated by several pathways that we will discuss here, among these the TFEB transcription factor, mTOR inhibition, ATF4, AMPK activation. Fasting and supplements like pterostilbene (contained in NOVOS Core) are also able to induce autophagy.

Safeguarding the Blueprint of Life: DNA Repair and PARP in Aging

Almost every cell in your body contains DNA, which is rightly called the blueprint of life. There are two main ideas on how DNA damage can drive aging. Any damage to your DNA will be copied into your proteins, which can affect their function (Milholland et al. 2017). Even worse, cells that accumulate many mutations can turn into cancer or into senescent “zombie cells” that do nothing much except secrete inflammatory cytokines that cause further damage to nearby cells (Petr et al. 2020).

Mice that are genetically engineered to have reduced DNA repair age faster, as do humans with DNA repair disorders (Petr et al. 2020), and longer-lived species like humans have more robust DNA repair, specifically so-called double-strand break repair. This repair may be in part mediated by the sirtuin SIRT6 (Tian et al. 2019), PARP (Chaudhuri and Nussenzweig 2017), and many other proteins.

There are few, if any, direct activators of DNA repair. However, avoiding unnecessary exposure to dietary and environmental carcinogens is a good way to reduce DNA damage and mutations. This means avoidance of smoking and second-hand smoke (Kim et al. 2018), avoidance of excessive sun exposure, and reduced intake of fried and grilled meats (Reng et al. 2022) because high temperatures produce harmful heterocyclic amines and polycyclic aromatic hydrocarbons. A predominantly plant-based diet by volume that includes a lot of raw and lightly cooked foods may be optimal in this regard (Oussalah et al. 2020, Cai et al. 2007). In this article we explain how The NOVOS Longevity Diet is the optimal diet for improved healthspan and lifespan.

TFEB and Aging: Reviving Autophagy and Protein Recycling for Healthy Aging

TFEB is a transcription factor, which means that it can affect the expression of hundreds of other genes. It is a master regulator of lysosomal biogenesis (lysosomes contain enzymes to break down biomolecules), autophagy, and protein recycling that is activated when nutrients are scarce (Ballabio et al. 2016). The main activator of TFEB is the now famous mTOR pathway, covered in the first article in this series (or rather, its suppression during starvation-like conditions). Other pro-longevity pathways that converge on TFEB include AMPK, GSK3, and Akt (Nabar and Kehrl 2017).

Several lines of evidence suggest that TFEB is a pro-longevity pathway. Overexpression of HLH-30, the worm version of TFEB, promotes the longevity of C. elegans (Lapierre et al. 2013), and drugs that elevate TFEB also extended worm longevity (Silvestrini et al. 2018). Calorie-restricted rats also have higher nuclear (active) TFEB levels (Lapierre et al. 2013).More importantly, it was shown that TFEB protein levels in human white blood cells decline with aging, leading to impaired autophagy and antibody production, which could be rescued by specific supplements. Pterostilbene (La Spina et al. 2021), pomegranate extract (Tan et al. 2019), and fisetin (Kim et al. 2016) all activate TFEB and might promote health through this mechanism. NOVOS Core contains both pterostilbene and fisetin.

From Repair to Rejuvenation

From the repair and recycling of cellular components facilitated by SIRTs, Autophagy, DNA repair, and PARP, to the pivotal role of TFEB in lysosomal biogenesis and autophagy activation, each pathway has unveiled its significance in promoting cellular health and extending lifespan.

In our next article we explore the topic of rejuvenation of cells, tissues, and stem cells. We will look at the research and interventions aimed at revitalizing the very fabric of life.

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References

References – sirtuins

Brenner, Charles. “Sirtuins are Not Conserved Longevity Genes.” Life Metabolism (2022).

Roichman, A., et al. “Restoration of energy homeostasis by SIRT6 extends healthy lifespan.” Nature communications 12.1 (2021): 1-18.

Korotkov, Anatoly, Andrei Seluanov, and Vera Gorbunova. “Sirtuin 6: linking longevity with genome and epigenome stability.” Trends in Cell Biology 31.12 (2021): 994-1006.

Mercken, Evi M., et al. “SIRT 1 but not its increased expression is essential for lifespan extension in caloric‐restricted mice.” Aging cell 13.1 (2014): 193-196.

Miller, Karl N., et al. “Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids.” Aging cell 16.3 (2017): 497-507.

Mitchell, Sarah J., et al. “Nicotinamide improves aspects of healthspan, but not lifespan, in mice.” Cell metabolism 27.3 (2018): 667-676.

References – autophagy

Pyo, Jong-Ok, et al. “Overexpression of Atg5 in mice activates autophagy and extends lifespan.” Nature communications 4.1 (2013): 1-9.

B’chir, Wafa, et al. “The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression.” Nucleic acids research 41.16 (2013): 7683-7699.

Chen, Rong-Jane, et al. “Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases.” journal of food and drug analysis 25.1 (2017): 125-133.

References – DNA repair and PARP

Tian, Xiao, et al. “SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species.” Cell 177.3 (2019): 622-638.

Petr, Michael A., et al. “Protecting the aging genome.” Trends in Cell Biology 30.2 (2020): 117-132.

Kim, A-Sol, et al. “Exposure to secondhand smoke and risk of cancer in never smokers: a meta-analysis of epidemiologic studies.” International journal of environmental research and public health 15.9 (2018): 1981.

Reng, Qie, et al. “Dietary meat mutagens intake and cancer risk: A systematic review and meta-analysis.” Frontiers in Nutrition 9 (2022).

Oussalah, Abderrahim, et al. “Health outcomes associated with vegetarian diets: An umbrella review of systematic reviews and meta-analyses.” Clinical Nutrition 39.11 (2020): 3283-3307.

Milholland, Brandon, Yousin Suh, and Jan Vijg. “Mutation and catastrophe in the aging genome.” Experimental gerontology 94 (2017): 34-40.

Ray Chaudhuri, Arnab, and André Nussenzweig. “The multifaceted roles of PARP1 in DNA repair and chromatin remodelling.” Nature reviews Molecular cell biology 18.10 (2017): 610-621.

Cai, Weijing, et al. “Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression.” The American journal of pathology 170.6 (2007): 1893-1902.

References – TFEB

Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).

Napolitano, Gennaro, and Andrea Ballabio. “TFEB at a glance.” Journal of cell science 129.13 (2016): 2475-2481.

Silvestrini, Melissa J., et al. “Nuclear export inhibition enhances HLH-30/TFEB activity, autophagy, and lifespan.” Cell reports 23.7 (2018): 1915-1921.

La Spina, Martina, et al. “Multiple mechanisms converging on Transcription Factor EB activation by the natural phenol pterostilbene.” Oxidative medicine and cellular longevity 2021 (2021).

Note: also cited in the AMPK part

Zhang, Hanlin, et al. “Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence.” Molecular cell 76.1 (2019): 110-125.

Kim, Sunhyo, et al. “Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.” Scientific reports 6.1 (2016): 1-13.

Nabar, Neel R., and John H. Kehrl. “Focus: Infectious Diseases: The Transcription Factor EB Links Cellular Stress to the Immune Response.” The Yale Journal of Biology and Medicine 90.2 (2017): 301.