Earlier this week I noticed a couple of very readable open access papers in which the authors discuss the potential for rejuvenation of stem cells as a means to address some aspects of aging. Reversing age-related stem cell decline has long been a topic of considerable interest in the broader longevity science and advocacy communities, ever since the stem cell medicine industry started up in earnest. Indeed, back in the early days of SENS rejuvenation research advocacy, when stem cells were in the news every other week, it was frequently necessary to emphasize that stem cell repair and replacement was just one of a range of necessary approaches to the treatment of aging. Even if an individual’s stem cells were somehow perpetually kept in pristine condition, the other forms of cell and tissue damage that lie at the root of aging would still result in degeneration and death. The degree of benefit achieved from fixing just one type of damage is an open question – we will most likely only find out some years after the relevant therapies become widely available, as is about to happen for senescent cell clearance.

Stem cells and their supporting structures are, of course, important in the aging process. Stem cells are responsible for generating replacement somatic cells needed to keep tissues functioning, but with advancing age the supply of new cells dwindles. This decline is one of the causes of frailty and organ failure. At present it looks likely that the changes in stem cell activity are as much a matter of altered cell signaling as of damage to the stem cells themselves. Temporarily restored signaling may be one of the means by which cell therapies produce benefits, by putting native cells back to work. Why does signaling change with aging, however? From an evolutionary perspective this reaction to rising levels of damage may exist because it serves to reduce cancer risk and thereby lengthen life, at the cost of a slower demise through organ failure, though programmed aging advocates would argue that stem cell decline is selected to promote aging as a fitness strategy. From a purely mechanical perspective, it is still up for debate as to the degree to which stem cell declines are secondary to the other forms of molecular damage and waste accumulation outlined in the SENS view of aging. It isn’t unreasonable to think that comprehensive repair elsewhere would lead to some degree of renewed stem cell activity as the signaling environment becomes more youthful.

Rejuvenating stem cells to restore muscle regeneration in aging

Adult muscle stem cells, originally called satellite cells (SCs), are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of SC dysfunction in aging animals, with the ultimate goal of rejuvenating old SCs and improving muscle function in elderly people. The emerging evidence indicates that the functional and numerical loss of SCs is a progressive process occurring throughout the lifetime of the organism. The long-lived quiescent SC accumulates many lesions caused by loss of homeostasis, metabolic alterations, and the aging environment. Although this process is gradual, it is accelerated in advanced old age to the extent that SCs become practically non-functional owing to senescence or apoptosis. In this context, disputes about which factors, intrinsic or extrinsic, are more dominant in dictating the fate of old SCs seem misplaced, and it is likely that both make important contributions to SC functional decline with aging.

A degree of success has been obtained in restoring the regenerative capacity of old muscle with both parabiosis experiments (extrinsic effect) and transplantation of ex vivo-rejuvenated SCs into old animals (intrinsic effect). The simplest explanation for these effects is the heterogeneous nature of SCs. Even in old age, the SC population includes a small percentage of functional SCs, with only limited accumulated damage that can be reversed still by extrinsic signaling factors or by ex vivo pharmacological inhibition of stress pathways such as p38 MAPK or JAK/STAT3. It is thus likely that the success of biochemical or genetic strategies applied to old SCs in transplantation experiments results from the proliferative amplification of a subset of highly regenerative cells. Alternatively, the health and fitness of old SCs could be increased by refueling “clean up” activities such as autophagy (which declines with aging) to eliminate damage, thus improving SC regenerative capacity after muscle injury and in transplantation procedures. Future interventions that could also be considered for combating age-related muscle regenerative decline may utilize the restoration of SC-niche interactions via the delivery of bioengineered molecules.

The key finding that the SC pool enters a state of irreversible senescence at a geriatric age implies that any treatment to rejuvenate endogenous stem cells should be implemented before this point of no return. It is also important to consider the link between SC regenerative potential and quiescence. It is generally well accepted that the more quiescent a stem cell is, the more regenerative capacity it has. It has also become clear that somatic stem cell populations are heterogeneous, with cells showing differing levels of quiescence. Highly quiescent subpopulations probably change with aging to become less quiescent and therefore of reduced regenerative capacity. SC heterogeneity should therefore be further investigated, with the aim of deciphering the molecular basis of quiescence. Understanding the quiescent state will allow early intervention aimed at preserving the highly regenerative quiescent subpopulations throughout life.

Likewise, strategies directed towards the expansion of relevant subpopulations of resident progenitor cells in the SC niche may be envisioned for reversing the age-associated muscle regenerative loss. Another unresolved issue is the interaction among the various events contributing to the loss of SC regenerative potential with aging. Research needs to focus on determining which events are causative and which are consequential. For example, DNA damage may induce the loss of baseline autophagy flux in old SCs, or alternatively DNA damage may be the consequence of oxidative stress resulting from the loss of autophagy flux. Defining the hierarchy of events leading to SC deterioration will enable the targeting of upstream events in order to achieve more efficient rejuvenation of SCs. Last but not least, in a low-turnover tissue like muscle, much of the damage to the quiescent SC is the result of the gradual decline (aging) of the niche composition and the systemic system. Future efforts to rejuvenate the regenerative potential of SCs should thus adopt a holistic view of the SC and its supportive environment.

Preventing aging with stem cell rejuvenation: Feasible or infeasible?

Preventing pathological conditions caused by aging, including cancer, osteoporosis, sarcopenia, and cognitive disorders, is one of the most important issues for human health, especially in societies with large aging populations. Although aging, defined by functional decline of cells/organs or accumulation of cell/organ damage, is one of the most recognizable biological characteristics in all creatures, our understanding of mechanisms underlying the aging process remains incomplete. The primary cause of functional declines occurring along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Stem cell exhaustion is induced by several mechanisms, including accumulation of DNA damage and increased expression of cell cycle inhibitory factors, such as p16 and p21.

Meanwhile, aging at cellular, tissue, organ and organismic levels has been reversed by exposing tissues from old animals to a young environment. Recent studies have suggested that stem cell rejuvenation could reverse organismal aging phenotypes, and that this could be achieved by inhibiting fibroblast growth factor 2, mammalian target of rapamycin (mTOR) complex 1, guanosine triphosphatase and cell division control protein 42. Several additional experiments, such as cross-age transplantation and heterochronic parabiosis, have revealed that some factors in the young systemic milieu can rejuvenate declined thymus gland function, as well as neural and muscle stem cell functions, in samples derived from elderly donors. Furthermore, heterochronic parabiosis experiments have also shown strong inhibition of young tissue stem cells by the aged systemic milieu or old serum.

Although cumulative cellular “intrinsic changes”, such as DNA damage, oxidative damage, increased expression of cell cycle inhibitors and mitochondria dysfunction, have been considered likely culprits for the tissue decline observed with aging, cellular rejuvenation induced by young systemic milieu would have been impossible if “intrinsic changes” were the only cause of cellular aging. Therefore, these so-called “causes of aging” should be more properly regarded as effects of aging (i.e., these processes are not causes, but rather consequences of aging), the result of cellular decisions often defined by responses to “extrinsic stimuli”. Here some questions arise: If aging at the cellular level were reversed, would it lead to the rejuvenation of the animal at an organismic level? Would it result in prevention of aging and, eventually, life extension?

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