Could Long-term, Partial Reprogramming of our Cells Battle Aging and Give us “Good Genes”?
June 1, 2022
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While the passing years seem not to take a toll on particular individuals (here´s looking at you, Tom Brady!), the incessant march of time generally brings common signs of wear and tear in us mere mortals. At the cell and tissue level, the normal aging process manifests as chronic inflammation and metabolic dysregulation (Ermolaeva et al., Keenan and Allan, and Melzer et al.), which foster functional deficits. Many have sought to discover an effective means of battling against such aging-related alterations, and now, exciting new research suggests that long-term partial reprogramming may represent a compelling means of inhibiting, reversing, and/or protecting against the signs of aging to allow us to “go long” into a healthy old age!
Hybrid model – For Cells as Well as Autos
Classic reprogramming strategies employed the expression of reprogramming factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM) to fully convert somatic cells such as skin fibroblasts into induced pluripotent stem cells iPS cells/iPSCs) (Takahashi and Yamanaka, and Takahashi et al.), which can differentiate into most cells/tissues of the body much like embryonic stem cells (ESCs). Subsequent research discovered that OSKM-induced fate alteration in somatic cells involved reprogramming the cell´s epigenome, prompting the rejuvenation of an “old” epigenetic state into a more “youthful” embryonic-like state. So, can partial reprogramming rejuvenate old cells while maintaining cell fate?
Research, Reprogram, Rejuvenate!
A fascinating new study from researchers headed by Heinrich Jasper (Genentech, Inc., South San Francisco) and Juan Carlos Izpisua Belmonte (Salk Institute for Biological Studies, La Jolla/Altos Labs, San Diego, CA, USA) that aimed to answer this question was based on reprogramming research employing in-vitro cell models and in-vivo models of premature aging (Ocampo et al. and Sarkar et al.). The outcomes of these previously published studies suggested that the short-term induced expression of reprogramming factors could safely “rejuvenate” the epigenome and prolong proper cell/tissue functionality. As the next step in this exciting field of research, Browder and Reddy et al. report in Nature Aging on their recent evaluation of short-term and long-term partial reprogramming in healthy wild-type mice undergoing normal aging.
The authors began by analyzing the epigenetic and transcriptomic changes associated with two different long-term partial reprogramming approaches (7 and 10 months starting at age 15 and 12 months, respectively) and a short-term late-onset strategy (1 month starting at age 25 months). The cells of the wild-type mice under study had been genetically engineered to carry a “cassette” that expresses OSKM in response to doxycycline exposure. Encouragingly, initial analyses demonstrated the safety of these partial reprogramming strategies, as evidenced by the lack of obvious negative consequences such as teratoma formation (a well-understood risk of OSKM expression), weight loss, altered blood cell counts, or neurologic impairment.
The “Epigenetic Clock”
Epigenetic clocks that employ DNA methylation patterns to estimate ‘epigenetic aging’ independent of chronological age (Horvath and Raj) have been employed to evaluate the effects of anti-aging strategies, including the short-term expression of reprogramming factors in human cells (Sarkar et al.). In this new study, the authors discovered that the long-term partial reprogramming strategies prevented/reversed age-related DNA methylation changes (or epigenetic aging) in the kidney and skin, resulting in a more youthful epigenetic landscape in these tissues. As expected due to the observed epigenetic alterations and the transcription factor status of the OSKM reprogramming factors, long-term partial reprogramming prompted widespread transcriptomic alterations; this included a specific and significant reduction in the expression of genes associated with senescence, inflammation, and stress (highly expressed during normal aging) and an alteration to the expression of genes linked to lipid/fatty acid metabolism and skin function.
Long-term partial reprogramming also prevented the onset of age-associated histological changes and maintained cell proliferation, with the skin and kidney seeing significant alterations perhaps due to their specific epigenetic profiles or relative receptiveness to reprogramming. The study also revealed improvements to skin histology that included increased epidermal cell proliferation and overall thickness and enhanced wound healing in old mice, resulting in the reduction in fibrotic tissue accumulation in the affected area. Finally, the authors discovered that the epigenetic and transcriptomic changes induced by long-term partial reprogramming were accompanied by a reduction in the age-related changes to serum metabolites and lipids, suggesting the existence of wide-ranging reductions in molecular aging phenotypes. The subsequent steps in this regard may involve defining those mechanisms that alter one-carbon metabolism and/or the balance between serum triacylglycerides and phospholipids.
These findings supported the predictions of previous studies that had hypothesized the prevention of aging phenotype onset and/or induced tissue rejuvenation in response to partial reprogramming (Sarkar et al., Lu et al., and Doeser et al.). However, the short-term late-onset partial reprogramming strategy supported only minor epigenetic, transcriptomic, and metabolic changes, suggesting that the duration of the treatment (go long, I said!) determines the extent of the beneficial effects; however, even this shorter-term strategy prompted some reduction to the activation of stress-associated pathways.
Overall, these findings suggest that long-term partial reprogramming represents a safe and potentially effective strategy to inhibit, reverse, and/or protect against many of the signs of normal aging to support an extended period of healthy aging. Future studies to further advance these exciting findings will explore the possible need for ongoing partial reprogramming to ensure that youthful epigenetic profiles endure and the potential existence of non-conducive cell states that resist reprogramming-mediated improvements in older mice (such as may exist in the short-term late-onset partial reprogramming strategy). Additional related lines of research include the definition of a possible threshold at which short-term improvements “mature” into a more permanent rejuvenated state and investigations into the basis for certain observed sex-based differences, such as a more significant response after the induction of reprogramming in female mouse skin.
“At the end of the day, we want to bring resilience and function back to older cells so that they are more resistant to stress, injury and disease,” says co-first author Reddy. “This study shows that, at least in mice, there’s a path forward to achieving that.”
For more on how long-term partial reprogramming may allow us to “go long” into a healthy old age, see Nature Aging, March 2022.
About the author
Stuart P. Atkinson, Ph.D.
Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!
Contact Stuart on Twitter with any questions