In this article, the fourth installment of our five-part series on different pathways of aging, we look at the rejuvenation of cells, tissues, and stem cells, a topic that has been gaining increasing popularity thanks to remarkable advancements in the field of epigenetic reprogramming. Recent research suggests that despite the accumulation of molecular damage over time, cells and tissues can indeed undergo rejuvenation. We’ll be exploring key subjects such as Epigenetic reprogramming, PGC1a and GSK3β, Telomerase (TERT), as well as Apoptosis and senescence. Join us on this enlightening journey as we uncover the groundbreaking discoveries that are shaping the future of aging research.
This is the fourth 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.
- Growth Pathways and Nutrient Sensing
- Resilience to Molecular Damage and Stress
- Repair and Recycling
- Rejuvenation of Cells, Tissues, and Stem Cells
- Metabolic Health
Table of Contents
The Promise of Epigenetic Reprogramming
Epigenetic marks are certain “modifications” attached to DNA that help genes to be turned on or expressed at the proper time. This includes, for example, histones with their modifications and DNA modifications called methylation.
The idea for reprogramming was simple yet beautiful. Children are born young, even though their parents are old, because they have undergone a process of cellular reprogramming that leads to rejuvenation. Their epigenetic marks are reset and re-established. Based on this idea, researchers found that transient expression of proteins called Yamanaka factors could rejuvenate cells and extend the lifespan of mice that show premature aging (Ocampo et al. 2016, Sarkar et al. 2020).
When we age, so does our epigenome, and one way to measure this epigenetic aging is through so-called DNA methylation clocks. Having established that reprogramming works in fast-aging mice, researchers then showed that reprogramming indeed reverses some DNA methylation clocks in healthy mice (Browder et al. 2022). It is hoped that the next set of improved reprogramming protocols could lead to mouse and eventually human lifespan extension, as well as better health.
Unfortunately, there are no safe and evidence-based ways of epigenetic reprogramming for the consumer right now since the technology is so new. However, some pro-longevity interventions will keep your epigenome younger for longer. For example, when you slow down aging through reduced growth hormone signaling in dwarf mice, this also slows down their epigenetic clock (Thompson et al. 2018).
Activating PGC-1α: The Exercise Connection and Potential Benefits for Aging
PGC-1α (PGC-1alpha) is responsible formitochondrial biogenesis, creating new mitochondria necessary for muscle function and respiration. The activity of this protein is regulated by the stress-sensitive kinase protein GSK3b and, perhaps more importantly, by the energy sensor AMPK (Souder et al. 2019, Anderson and Prolla 2009).
Since age-related mitochondrial dysfunction is one hallmark of aging, many researchers believe that elevated PGC-1α levels or PGC-1α activity should benefit lifespan. So far, we do know that PGC-1α is, in fact, consistently upregulated in long-lived mice on the level of mRNA and protein (Tyshkovskiy et al. 2019. Ozkurede et al. 2019). It was also shown that overexpression of this gene promotes fly lifespan (Rera et al. 2011). All of this is consistent with a beneficial effect of high PGC-1α.
Caloric restriction and exercise are the classic activators of PGC-1a expression (Anderson and Prolla 2009). In this context, it is interesting to note that resveratrol and the related, more powerful molecule pterostilbene, have been touted as potential “exercise mimetics” due to their ability to induce PGC-1α (Handschin et al. 2016, Liu et al. 2019) and increase health span. NOVOS Core contains pterostilbene.
Telomerase, Longevity and Cancer Prevention
In contrast to bacteria, humans possess linear DNA, which cannot be easily replicated without losing a piece of the DNA at their end; this is called the end-replication problem (Ohki et al. 2001). If the ends of our DNA were to get critically short, cells would start losing genetic material at each cell division. That is a simplified explanation for why we need telomerase (in part, encoded by the TERT gene), which is the enzyme that extends the ends of our chromosomes, made up of repetitive DNA sequences called telomeres.
However, even more important is the role of telomeres in cancer prevention. Most cells do not express telomerase; every time they divide (and replicate DNA), their telomeres get shorter. Only a subset of stem cells expresses telomerase. Although this effectively reduces the risk of runaway replication, as seen with cancer cells, because most cells are unable to do so, the trade-off is that cells with eroded telomeres can become dysfunctional and undergo senescence (Shay and Wright 2011, Ujvari et al. 2022).
Human telomeres shorten with aging (Demanelis et al. 2020), and multiple labs have shown that telomerase activation extends mice’s lifespan (Jesus et al. 2012), suggesting this pathway could be conserved.
Aging and Cell Death: Unraveling the Role of Apoptosis and Senescence
Cells that are metabolically stressed or suffer from DNA damage are often faced with a choice between undergoing cell death (through a mechanism called apoptosis) or growth arrest (through senescence; Argüelles et al. 2019). One evolutionary reason for this “trigger finger” is allowing the body to eliminate damaged pre-cancerous cells in their early stages. Stresses that can trigger cell death and often senescence include misfolded proteins, viral infection, iron excess, and inflammation.
Excessive cell death during aging contributes to many human age-related diseases like frailty, muscle loss (Marzetti et al. 2012), or Parkinson’s disease, where it leads to the death of irreplaceable neurons (Trist et al. 2019) — whereas, in mice, excessive apoptosis due to mitochondrial DNA mutations lead to premature aging (Kujoth et al. 2005).
Conversely, resistance to apoptosis also plays a role in aging (Salminen et al. 2010). Adipose tissue, brain, heart, and skin are among the many tissues that accumulate senescent cells with aging (Tuttle et al. 2020) that not only refuse to die but also promote disease through the production of cytokines (“inflammaging”; Xu et al. 2018; Kirkland and Tchkonia 2020).
Exercise reduces apoptosis in the heart muscle (Kwak 2013) and prevents or reduces age-related muscle loss, most likely through reduced apoptosis (Marzetti et al. 2012), senescence, and direct anabolic stimulation leading to compensatory hypertrophy (muscle building). While caloric restriction also reduces apoptosis and senescence during aging, it will decrease total muscle mass, which may be undesirable for athletes and the elderly. Intermittent fasting could be a healthy alternative that maintains total muscle mass (Sandoval et al. 2021).
One way to slow down the progression of senescent cells is with NOVOS Core. In an independent lab study conducted at Newcastle University, NOVOS Core was found to counter senescent cells at a level comparable to the prescription longevity drug, rapamycin.
Navigating the Pathways of Aging: From Epigenetics to Metabolism
As we continue to unravel the mysteries of aging, the path towards healthier aging becomes more tangible. The fusion of scientific research and innovative interventions like NOVOS Core opens up a realm of possibilities for extending lifespan, improving health span, and potentially mitigating the burden of age-related diseases.
In the next article of this series, we will look at metabolic health and its impact on aging. Metabolism, a central player in the aging process, holds the key to numerous age-related conditions. By understanding and addressing metabolic health, we can uncover new avenues to promote longevity and enhance overall well-being.
Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.
References – Epigenetic reprogramming
Ocampo, Alejandro, et al. “In vivo amelioration of age-associated hallmarks by partial reprogramming.” Cell 167.7 (2016): 1719-1733.
Browder, Kristen C., et al. “In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice.” Nature Aging 2.3 (2022): 243-253.
Thompson, Michael J., et al. “A multi-tissue full lifespan epigenetic clock for mice.” Aging (Albany NY) 10.10 (2018): 2832.
Sarkar, Tapash Jay, et al. “Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells.” Nature communications 11.1 (2020): 1-12.
References – PGC-1a and GSK3β
Ozkurede, Ulas, and Richard A. Miller. “Improved mitochondrial stress response in long‐lived Snell dwarf mice.” Aging Cell 18.6 (2019): e13030.
Anderson, Rozalyn, and Tomas Prolla. “PGC-1α in aging and anti-aging interventions.” Biochimica et Biophysica Acta (BBA)-General Subjects 1790.10 (2009): 1059-1066.
Tyshkovskiy, Alexander, et al. “Identification and application of gene expression signatures associated with lifespan extension.” Cell metabolism 30.3 (2019): 573-593.
Rera, Michael, et al. “Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog.” Cell metabolism 14.5 (2011): 623-634.
Handschin, Christoph. “Caloric restriction and exercise “mimetics’’: Ready for prime time?.” Pharmacological research 103 (2016): 158-166.
Liu, Dong, Shubin Qiao, and Jiansong Yuan. “Pgc1a Activation by Pterostilbene Ameliorates Acute Doxorubicin Cardiotoxicity via Reducing Mitochondrial Oxidative Stress Through Enhancing Ampk and Sirt1 Cascades.” Circulation Research 125.Suppl_1 (2019): A304-A304.
Souder, Dylan C., and Rozalyn M. Anderson. “An expanding GSK3 network: implications for aging research.” Geroscience 41.4 (2019): 369-382.
References – telomerase (TERT)
Ohki, Rieko, Toshiki Tsurimoto, and Fuyuki Ishikawa. “In vitro reconstitution of the end replication problem.” Molecular and cellular biology 21.17 (2001): 5753-5766.
Shay, Jerry W., and Woodring E. Wright. “Role of telomeres and telomerase in cancer.” Seminars in cancer biology. Vol. 21. No. 6. Academic Press, 2011.
Ujvari, Beata, et al. “Telomeres, the loop tying cancer to organismal life‐histories.” Molecular Ecology (2022).
Demanelis, Kathryn, et al. “Determinants of telomere length across human tissues.” Science 369.6509 (2020): eaaz6876.
Bernardes de Jesus, Bruno, et al. “Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer.” EMBO molecular medicine 4.8 (2012): 691-704.
References – Apoptosis and senescence
Tuttle, Camilla SL, et al. “Cellular senescence and chronological age in various human tissues: A systematic review and meta‐analysis.” Aging Cell 19.2 (2020): e13083.
Kujoth, Gregory C., et al. “Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.” Science 309.5733 (2005): 481-484.
Salminen, Antero, Johanna Ojala, and Kai Kaarniranta. “Apoptosis and aging: increased resistance to apoptosis enhances the aging process.” Cellular and molecular life sciences 68.6 (2011): 1021-1031.
Marzetti, Emanuele, et al. “Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty–a mini-review.” Gerontology 58.2 (2012): 99-106.
Xu, Ming, et al. “Senolytics improve physical function and increase lifespan in old age.” Nature medicine 24.8 (2018): 1246-1256.
Note: study showing SASP not just in mice but also in human adipose tissue, prevented by DQ
Kirkland, J. L., and T. Tchkonia. “Senolytic drugs: from discovery to translation.” Journal of internal medicine 288.5 (2020): 518-536.
Kwak, Hyo-Bum. “Effects of aging and exercise training on apoptosis in the heart.” Journal of exercise rehabilitation 9.2 (2013): 212.
Argüelles, Sandro, et al. “Advantages and disadvantages of apoptosis in the aging process.” Annals of the New York Academy of Sciences 1443.1 (2019): 20-33.
Sandoval, Cristian, Sybella Santibañez, and Francisca Villagrán. “Effectiveness of intermittent fasting to potentiate weight loss or muscle gains in humans younger than 60 years old: a systematic review.” International Journal of Food Sciences and Nutrition 72.6 (2021): 734-745.