Fight Aging!

Today's open access preprint paper touches on the important topic of synergy between therapies targeting mechanisms of aging. For a variety of reasons, far too little work in academia and industry is conducted on combinations of therapies, and not just for the treatment of aging. Intellectual property, bounds of domain knowledge, academic publishing incentives, and organizational inertia make it much harder to commit to the evaluation of two or more different therapies in combination than to focus only on one approach. This has always been the case in medical development, but it is a critical problem in the context of treating age-related disease by targeting the underlying mechanisms of aging. Aging has numerous distinct causes, and age-related diseases are the combined outcome of multiple distinct processes. Only limited benefits can be obtained by focusing on only one of those causes.

The end goal for the treatment of aging as a medical condition must be to address every important mechanism, employing a collection of therapies. In the early stages of the lengthy development process leading to that end goal, evaluation combinations of therapies will be an important part of optimizing ongoing allocation of time and resources. Yet next to no work is conducted on combination studies, and there is little prospect for an expansion of that work on the part of academia and industry, because of the established incentives. This may be a part of the field in which philanthropic ventures will have to do the heavy lifting. See, for example, the proposed later stages of the Astera Institute's Rejuvenome program.

Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan

Stem cells play a pivotal role in this tissue homeostasis by providing a reservoir of pluripotent precursor cells, needed to replace fully differentiated cells that are lost or damaged. At the opposite end of the cell-fate spectrum are senescent cells, or cells that have permanently withdrawn from the cell cycle. By entering permanent replicative arrest, senescent cells prevent mutations from expanding, thereby providing a sink for genotoxic damage. However, the senescent state does not simply result in passive replicative arrest but instead leads to transcriptional changes causing resistance to apoptosis and increased secretion of pro-inflammatory signaling molecules, a process known as Senescence Associated Secretory Phenotype (SASP). Senescent cell induced SASP in turn promotes inflammation and contributes to age-dependent dysfunction and to the development of age-related diseases.

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.

Accumulation of senescent cells and loss of stem cells are not independent processes. Through SASP, senescent cells release large amounts of 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 the Yamanaka factors (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 at the expense of healthspan 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.