Reprogramming to Improve Stem Cell Function Synergizes with Senescent Cell Clearance in Flies

Rejuvenation will be achieved in humans by combinations of therapies, provided periodically over time. Each individual therapy will in some way address one of the forms of cell and tissue damage that accumulate to cause the pathologies of aging. There are numerous independent sources of such damage, however. It is the case that the various types of accumulating damage, and the far greater variety of dysfunctions caused by that damage, will interact with one another to make outcomes worse than they would have been alone. Nonetheless, very different forms of rejuvenation therapy will be required to repair each of the very different forms of damage. Each individual repair therapy will produce only incremental outcomes, it will not solve all of aging.

Given this, there is, even at this comparatively early juncture in the development of rejuvenation therapies, far too little work taking place on how to best combine treatments, and on assessing the outcomes of combined treatments. Fortunately that is slowly changing, and a number of groups are at present putting earnest effort into running combinatorial studies in short-lived model organisms. Still, it is far from enough, and largely focused on metabolic adjustments that can only modestly slow aging, not repair the underlying damage.

With that in mind, today's open access paper is an interesting first step towards showing that partial reprogramming, with the effect of improving stem cell function, synergizes well with clearance of senescent cells. Both of these approaches have been shown to improve health and function in old animals, with the caveat that senolytic treatments capable of selectively destroying senescent cells are a less recent innovation, and thus come with far more data - and more robust data - demonstrating rejuvenation. The work here uses inducible expression in genetically engineered flies rather than the delivery of therapeutics into wild-type animals in order to achieve the observed results, but that is a first step towards better studies in mice.

Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan

While the number of stem cells decreases in aging animals, senescent cells accumulate with age. Manipulating cell fates by cellular reprogramming (to rejuvenate somatic cells) and by senolytic interventions (to remove senescent cells) are two promising approaches to restore homeostasis in aged individuals and to prevent age-dependent diseases. Cellular reprogramming allows differentiated cells to regain plasticity and to take on more stem cell-like qualities. A major step towards this goal was the demonstration of cellular reprogramming of terminally differentiated cells into pluripotent embryonic-like stem cell states. Such reprogramming reverses epigenetic aging marks, demonstrating that even mature, terminally differentiated cells can be returned to a younger state. While continuous expression of the Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) in mice led to the formation of teratomas and decreased lifespan, repeated short term expression in adult mice succeeded in ameliorating cellular and physiological signs of aging. Subsequently, several studies have suggested that this approach can be applied to human aging and age-related disease, and cycling expression can rejuvenate stem cells in vitro.

Ablation of senescent cells has been shown to reverse tissue dysfunction and extend healthspan in mice. A recent study using a senolytic construct (FOXO4-DRI peptide) that induced apoptosis in senescent cells, by interfering with the binding of p53 to FOXO4 thereby freeing p53 to activate apoptosis, showed that the clearing of senescent cells both counteracted senescent cell induced chemotoxicity and restored age-dependent declines in physical performance, fur density, and renal function in aging mice. Several studies have further explored applications of different senolytic strategies to ameliorate age-related decline and disease.

Accumulation of senescent cells and loss of stem cells are not independent processes. Through the senescence-associated secretory phenotype (SASP), senescent cells release pro-inflammatory cytokines which contribute to chronic inflammation and mTOR activation, ultimately leading to stem cell exhaustion. This interaction suggests that senolytic therapies might interact with cellular reprogramming strategies in delaying age-dependent decline and disease. We have previously explored drug-drug interactions as synergistic aging interventions, and here we ask whether a combinatorial treatment of OKSM and senolytic (Sen) expression could mitigate or reverse the effects of aging more efficiently than either intervention alone.

To test this hypothesis, we induced expression of OKSM, Sen, and an OKSM-Sen combination in adult flies and compared their effects on health and lifespan. We find that each treatment alone had limited benefits, with OKSM alone benefiting maximum lifespan while Sen expression alone increased mean lifespan but had no effect on maximum lifespan. In contrast, animals subjected to the combined intervention experienced substantially longer mean and maximum lifespan. Our data is consistent with a synergistic interaction between the two interventions, simultaneously rejuvenating stem cells and removing senescent cells.


This makes me very excited. I've been waiting for combination therapies for years, and these results are as encouraging as I could have dreamed.

Here we fucking go!

Posted by: Ben at November 8th, 2022 1:55 AM

yeah, this has been the best news of 2022. Not just additive effect, but synergistic! I wonder if the effects observed in this experiment might be mainly due to SASP normally interfering with reprogramming factors-iirc only a relatively small fraction of cells are successfully reprogrammed when OSKM reprogramming is done. Maybe by eliminating senescent cells & associated SASP, this allows reprogramming to occur in more cells?

Posted by: gheme at November 8th, 2022 9:44 AM
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