Mois : septembre 2024

Juan José Alba-Linares and his research team have published a preprint study that examined why different animals age at different rates. They found that epigenetic changes over time could explain why some animals live longer and estimated an upper limit for mammalian lifespan [1].

A problem of noise

In this study, Alba-Linare’s team analyzed the epigenetics of 18 different mammals and found that the rate at which their methylation became disorganized (noisy) matched how long those animals tend to live. For example, humans and whales have slower epigenetic changes, which might be why they can live for many decades. In contrast, mice were found to have much faster changes, which might explain their shorter lifespans.

The researchers think this could mean that there is a natural limit to how long mammals can live, and they estimate that the maximum lifespan for any mammal, including humans, might be around 220 years.

This study gives scientists a new way to think about aging. If people can figure out how to slow down the epigenetic changes that cause this noise, they might be able to find ways to help people live longer, healthier lives. However, the researchers also pointed out that more studies are needed, especially to see how epigenetic changes in different body parts besides blood and how things like diet and environment affect this process.

In summary, this research helps explain why we age by examining how our DNA changes. It also hints that there might be a natural limit to how long humans and other mammals can live, though scientists are still working to fully understand this.

Hardly uneditable

Biotechnology and medical research advancements have opened new frontiers in the quest to understand and potentially reverse aspects of aging. Among the most promising developments CRISPR-based therapies, which are currently being developed to affect the epigenome, not just the genome. These therapies could reverse or slow down the accumulation of epigenetic noise. By restoring proper DNA methylation patterns, such therapies could possibly re-establish cellular function and identity, addressing a fundamental cause of aging.

If such technology is utilized to correct age-related epigenetic changes or to reverse epigenetic drift, it could theoretically extend human lifespan beyond the predicted maximum of 220 years. This potential to extend human lifespan is not just a theoretical concept but a real possibility that could change how we perceive aging. Specifically, CRISPR-mediated methylation editing might re-establish youthful epigenetic patterns, reducing cellular noise and extending health span and lifespan. Applications of CRISPR in this context include direct epigenome editing, which involves the targeted modification of DNA methylation patterns to “reset” aging cells, and gene therapy that repairs age-related genetic mutations that accelerate entropy or contribute to age-related diseases [2].

Another groundbreaking approach is epigenetic reprogramming using the Yamanaka factors: Oct4, Sox2, Klf4, and c-Myc. This method has demonstrated the ability to reverse age-associated epigenetic changes and restore youthful cellular phenotypes. This technique could dramatically reduce epigenetic noise and entropy, extending lifespan beyond natural limits by reprogramming cells to a more youthful state [3, 4].

If applied systemically without inducing cancer, epigenetic reprogramming could reset the biological clock and significantly extend lifespan. Current research has shown that transient expression of Yamanaka factors can rejuvenate cells in mice without fully reprogramming them to an embryonic state or risking de-differentiation into other cell types, suggesting potential for safe application in humans [5].

Cell therapy involving stem cells or exosomes derived from young donors may also help rejuvenate aged tissues. These treatments could reset or slow down the aging clock in tissues by re-establishing youthful gene expression patterns and restoring epigenetic stability, possibly pushing lifespan beyond predicted limits [4].

Other approaches

Senolytics represent another promising avenue in anti-aging research. These are drugs designed to clear senescent cells, which are dysfunctional cells that accumulate with age and contribute to chronic inflammation and tissue degradation [6, 7]. By reducing the burden of senescent cells, senolytics could decrease epigenetic entropy by preventing cellular dysfunction and genomic instability.

Although they do not directly address DNA methylation, senolytics may help maintain the overall health of the cellular environment, thus slowing down the accrual of epigenetic noise. Drugs like dasatinib and quercetin are currently being tested for their ability to eliminate senescent cells and potentially extend lifespan selectively [8].

Telomere extension therapies offer yet another strategy to combat aging. Telomere shortening is a well-known hallmark of aging, and therapies based on telomerase activation aim to lengthen telomeres, extending cellular lifespan and improving overall genomic stability [9]. While this approach does not directly address epigenetic entropy, extending telomeres could help stabilize the genome, prevent cellular senescence, and mitigate age-related genomic and epigenomic changes [10]. Longer telomeres might delay the onset of epigenetic noise accumulation, which limits lifespan.

Restoration of NAD+ levels is also gaining attention in aging research. NAD+ levels decline with age, leading to compromised mitochondrial function and increased cellular stress. Therapies that replenish NAD+ levels, such as NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), aim to improve energy metabolism and enhance DNA repair mechanisms. By restoring NAD+ levels, these therapies could reduce the accumulation of DNA damage and epigenetic drift, thereby delaying or preventing some of the processes contributing to epigenetic entropy. This would enable cells to control gene expression and longevity pathways better [11].

Lastly, caloric restriction mimetics such as rapamycin, resveratrol, and spermidine mimic the effects of caloric restriction, which has been shown to delay aging and reduce epigenetic entropy. By reducing the metabolic burden and oxidative stress on cells, these treatments could maintain epigenetic integrity for extended periods, pushing the upper limits of lifespan. These compounds aim to activate longevity pathways without significantly reducing caloric intake, making them more practical for widespread use [12-14].

Such emerging therapies and interventions offer potential avenues to slow down aging and could obviate this paper’s prediction of a maximum human lifespan based on epigenetic entropy. By directly targeting the fundamental mechanisms of aging, whether through genetic editing, epigenetic reprogramming, removal of senescent cells, telomere extension, restoration of vital molecules like NAD+, or mimicking the effects of caloric restriction, scientists are exploring ways to extend human healthspan and lifespan beyond current limitations. Continued research and development in these areas may one day redefine our understanding of aging and open the door to unprecedented longevity.

Literature

[1] José, J.; Linares, A.-; Ramón Tejedor, J.; Fernández, A.F.; Pérez, R.F.; Fraga, M.F. A Universal Limit for Mammalian Lifespan Revealed by Epigenetic Entropy. bioRxiv 2024, 2024.09.06.611669.

[2] Fadul, S.M.; Arshad, A.; Mehmood, R. CRISPR-Based Epigenome Editing: Mechanisms and Applications. Epigenomics 2023, 15, 1137–1155.

[3] Yamanaka, S. Induced Pluripotent Stem Cells: Past, Present, and Future. Cell Stem Cell 2012.

[4] Singh, P.B.; Zhakupova, A. Age Reprogramming: Cell Rejuvenation by Partial Reprogramming. Development (Cambridge) 2022, 149.

[5] Puri, D.; Wagner, W. Epigenetic Rejuvenation by Partial Reprogramming. BioEssays 2023, 45, 2200208.

[6] Chaib, S.; Tchkonia, T.; Kirkland, J.L. Cellular Senescence and Senolytics: The Path to the Clinic. Nature Medicine 2022 28:8 2022, 28, 1556–1568.

[7] Wissler Gerdes, E.O.; Zhu, Y.; Tchkonia, T.; Kirkland, J.L. Discovery, Development, and Future Application of Senolytics: Theories and Predictions. FEBS J 2020, 287, 2418–2427.

[8] Nieto, M.; Könisgberg, M.; Silva-Palacios, A. Quercetin and Dasatinib, Two Powerful Senolytics in Age-Related Cardiovascular Disease. Biogerontology 2024, 25, 71–82.

[9] Saretzki, G. Role of Telomeres and Telomerase in Cancer and Aging. International Journal of Molecular Sciences 2023, Vol. 24, Page 9932 2023, 24, 9932.

[10] Rai, R.; Sodeinde, T.; Boston, A.; Chang, S. Telomeres Cooperate with the Nuclear Envelope to Maintain Genome Stability. BioEssays 2024, 46, 2300184.

[11] Covarrubias, A.J.; Perrone, R.; Grozio, A.; Verdin, E. NAD+ Metabolism and Its Roles in Cellular Processes during Ageing. Nature Reviews Molecular Cell Biology 2020 22:2 2020, 22, 119–141.

[12] Panwar, V.; Singh, A.; Bhatt, M.; Tonk, R.K.; Azizov, S.; Raza, A.S.; Sengupta, S.; Kumar, D.; Garg, M. Multifaceted Role of MTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease. Signal Transduction and Targeted Therapy 2023 8:1 2023, 8, 1–25.

[13] Ni, Y.; Zheng, L.; Zhang, L.; Li, J.; Pan, Y.; Du, H.; Wang, Z.; Fu, Z. Spermidine Activates Adipose Tissue Thermogenesis through Autophagy and Fibroblast Growth Factor 21. J Nutr Biochem 2024, 125, 109569.

[14] Pezzuto, J.M. Resveratrol: Twenty Years of Growth, Development and Controversy. Biomol Ther (Seoul) 2019, 27, 1–14.

Researchers are keeping a bank of induced pluripotent stem cells (iPSCs) derived from centenarians and their descendants. They describe the purpose of this bank and its uses in Aging Cell.

A category of their own

Centenarians don’t merely live for a hundred years; they spend more time in good health (healthspan) than other people. This is called the compression of morbidity [1]. This makes them ideal for research, as people attempt to assess why they are so resistant to various age-related disorders such as Alzheimer’s disease [2]. However, researchers have still not discovered the biological methods by which centenarians retain such longevity [3].

At least part of this longevity is genetic. The descendants of centenarians are less vulnerable to age-related diseases [4] and are younger according to epigenetic clocks [5]. Therefore, cells derived from centenarians, including iPSCs that can transform into any other type of cell, will retain these genetic advantages [6].

Old cells can grow like young cells

These researchers built their bank using peripheral blood mononuclear cells (PBMCs) and the iPSCs derived from them. A total of 45 centenarians were recruited for this study, with 45 descendants included as well. Over three-fourths of the centenarians had healthy brains at age 100, and more than four-fifths were able to live independently at that age.

While offspring data was less consistent, centenarians were confirmed to have slightly slower epigenetic aging than non-centenarians. In accordance with previous research, immune cells derived from centenarians were found to have named longevity-promoting genes [7].

Creating iPSCs from such old people was surprisingly easy; generating them and having them proliferate was no different than it was in cells derived from younger people. The researchers were able to program these cells into forebrain neurons. Regardless of the age of the subjects, all cells were equally likely to correctly differentiate into these cells. However, some cells in three male centenarians lacked their Y chromosomes; this “mosaic” loss is linked to age-related diseases [8].

The researchers tout their new biobank as a permanent resource that can aid future research, and propose that it might be used in finding effective therapies against age-related diseases. Additionally, it better enables the identification of people who are likely to live for a very long time, thus allowing them to be more easily included in future research. If these iPSCs can be used to create organoids that simulate human organs, it might be possible to validate therapies against age-related diseases that work even on the oldest old.

Literature

[1] Fries, J. F., Bruce, B., & Chakravarty, E. (2011). Compression of morbidity 1980–2011: a focused review of paradigms and progress. Journal of aging research, 2011(1), 261702.

[2] Andersen, S. L. (2020). Centenarians as models of resistance and resilience to Alzheimer’s disease and related dementias. Advances in geriatric medicine and research, 2(3).

[3] Lin, J. R., Sin-Chan, P., Napolioni, V., Torres, G. G., Mitra, J., Zhang, Q., … & Zhang, Z. D. (2021). Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nature Aging, 1(9), 783-794.

[4] Newman, A. B., Glynn, N. W., Taylor, C. A., Sebastiani, P., Perls, T. T., Mayeux, R., … & Hadley, E. (2011). Health and function of participants in the Long Life Family Study: a comparison with other cohorts. Aging (Albany NY), 3(1), 63.

[5] Horvath, S., Pirazzini, C., Bacalini, M. G., Gentilini, D., Di Blasio, A. M., Delledonne, M., … & Franceschi, C. (2015). Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging (Albany NY), 7(12), 1159.

[6] Bucci, L., Ostan, R., Cevenini, E., Pini, E., Scurti, M., Vitale, G., … & Monti, D. (2016). Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. Aging (Albany NY), 8(3), 510.

[7] Karagiannis, T. T., Dowrey, T. W., Villacorta-Martin, C., Montano, M., Reed, E., Belkina, A. C., … & Sebastiani, P. (2023). Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity. EBioMedicine, 90.

[8] Thompson, D. J., Genovese, G., Halvardson, J., Ulirsch, J. C., Wright, D. J., Terao, C., … & Perry, J. R. (2019). Genetic predisposition to mosaic Y chromosome loss in blood. Nature, 575(7784), 652-657.

Dr. Belmonte’s group at Altos Labs targeted stressed and senescent cells with partial reprogramming, producing large increases in lifespan in male mice [1].

What are they doing there?

Since the discovery of cellular reprogramming almost two decades ago, a lot of hopes have been put into this technology, and a lot of progress has been made. Partial reprogramming, when cells do not revert to a pluripotent state but retain their identity while also undergoing rejuvenation, is being pursued by numerous companies, including the gigantic and secretive Altos Labs, which was founded by Jeff Bezos and Yuri Milner with a three-billion-dollar investment.

Altos Labs has recruited many big names in the longevity field, such as Steve Horvath, Morgan Levin, and Juan Carlos Izpisua Belmonte. Dr. Belmonte was the first to demonstrate that partial cellular reprogramming extends lifespan in fast-aging (progeroid) mice [2]. For a couple of years, little has been known about what’s going on at Altos. A new paper in Science by Dr. Belmonte’s team might be a major leap towards bringing partial cellular reprogramming to the clinic.

Targeting only damaged cells

The scientists used just three of the original four reprogramming “Yamanaka factors”: OSK instead of OSKM. Omitting the fourth factor, c-Myc, was pioneered by Harvard geroscientist David Sinclair, and his team’s work on partial reprogramming of retinal ganglion cells [3] was given credit in this new paper. The three-factor cocktail is thought to be safer and easier on cells.

However, this study’s big distinction is that the viral vectors carrying the three factors were only aimed at stressed and senescent cells. While there have been experiments with tissue-specific reprogramming, the novelty in Dr. Belmonte’s approach is that it targets damaged, but not healthy cells in multiple tissues. The hypothesis was that rejuvenating those cells might be enough for a robust effect on an organismal level.

The targeting was achieved by using the promoter Cdkn2a, which is mostly active in stressed and senescent cells. If the environment in those cells turns the endogenous promoter on, it should also activate the same promoter on the viral vector, triggering OSK expression.

Late-life treatment increases lifespan

First, the researchers experimented with a mouse model of Hutchinson-Guilford progeria syndrome. Such mice experience greatly accelerated aging. The OSK treatment led to improvements in both median (40%) and maximal (32%) lifespan, body weight, activity, and inflammation.

As a positive control, the researchers used viral vectors with anti-inflammatory cargo (an NF-κB inhibitor) to make sure the effects produced by the OSK treatment go beyond simply quelling inflammation. Indeed, the anti-inflammatory treatment led to a much smaller increase in lifespan.

The improvements in lifespan were comparable to the group’s previous results with full-body cellular reprogramming, suggesting that targeting only damaged cells can be just as effective. However, in that experiment, the researchers used all four reprogramming factors.

Progeroid mice are not the best models of natural aging. The researchers subsequently moved to wild-type mice, delivering a single injection to aged (18-month-old) male animals. Despite the late-life administration, the treatment significantly improved both median and maximal lifespan (median by 12%). Age-related body weight loss was largely prevented, and overall physical activity and fitness were improved compared to age-matched controls.

Not a senolytic

The researchers investigated whether the treatment killed senescent cells (a senolytic effect). However, eight months after the shot, most cells where viral-delivered OSK were activated were still there. This shows that the treatment improved the targeted cells instead of just eliminating them.

Senescent cells are not always harmful. In fact, they exist even in young people and play important roles in development, wound healing, and cancer prevention, although they can also promote cancer under certain circumstances. This is why a senomorphic approach, which alters senescent cells towards a healthier phenotype, might be superior. Reassuringly, the OSK treatment improved wound healing in the mice.

Another known problem with cellular reprogramming is that it might lead to the creation of tumors (tumorigenesis), although OSK without the M has a better safety profile. In this study, too, the treated mice were not more prone to cancer than controls over two years of follow-up.

The researchers note that the way their treatment downregulates pro-inflammatory genes in senescent cells without leading to cell death resembles how some other geroprotective interventions work, including metformin and the mTOR inhibitor rapamycin.

These findings suggest that we may not need to target a large population of cells to elicit functional organismal improvement. Young organisms have the potential to cope with a diverse range of stresses, with a strong molecular buffering capacity that gradually deteriorates with age. This buffering capacity may be improved by targeting a small population of cells, such as aged and stressed cells, leading to the improvement of the entire organism. Further understanding of the target organs and cell types driving the beneficial effects of Cdkn2a-OSK may allow us to develop a more precise approach to achieve organismal rejuvenation and reverse disease phenotypes.

Literature

[1] Sahu, S. K., Reddy, P., Lu, J., Shao, Y., Wang, C., Tsuji, M., … & Belmonte, J. C. I. (2024). Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging. Science Translational Medicine, 16(764), eadg1777.

[2] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.

[3] Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., … & Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124-129.