Fight Aging!

A variety of approaches show some promise in improving the function of stem cells in aged tissues. Stem cell populations support their tissue by providing a supply of daughter somatic cells to replace losses. This supply diminishes over time as stem cells reduce their activity for reasons that descend from the known root causes of aging, but which are not fully understood in detail. To the degree that reduced stem cell function is a response to the aged environment rather than a consequence of damage inherent to these cells, then it is useful to find ways to force stem cells to be more active. Whether this is the case may differ for different cell types, but there is ample evidence for interventions that can at least modestly enhance stem cell activity.

Perhaps the most interesting of these interventions are partial reprogramming and CDC42 inhibition via CASIN. The latter is much more feasible than the former when considering the prospects for near-term human use, but both offer the prospect of one-time treatments that produce a lasting reversal of stem cell aging and consequent improvement in tissue function. It is most likely a long road ahead to the first partial reprogramming therapies, but CASIN only awaits initial human testing to establish that safety is similar to that observed in mice.

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities.

The beneficial effect of exercise on health has been known for a long time. It has been shown that moderate intensity running for 30 minutes per day for 8 weeks increases the number of skeletal muscle stem cells in aged mice. The brain is another organ that is affected by exercise. Neurogenesis increases in mice transplanted with plasma from exercised aged mice. Some other aged stem cells also benefit from exercise, such as tendon stem cells.

Calorie restriction (CR) and fasting are two other strategies that have been largely studied for their rejuvenating capacities. Intestinal stem cells increase in number and replicate more after CR and fasting-mimicking diet (FMD), and their capacity to form organoids is improved after fasting. In the skeletal muscle, muscle stem cells seem to enter a deep quiescent state after fasting, which is not recovered by re-feeding. This slows muscle regeneration but improves the survival of these stem cells.

An exciting strategy that has been proposed for cell rejuvenation is reprogramming cells to a more undifferentiated state by inducing expression of the Yamanaka factors. A cyclic induction of OSKM was able to increase the numbers of muscle stem cells and hair follicle stem cells in adult mice with progeria and to improve regeneration of the skeletal muscle. Further studies will be needed to better understand the effect of reprogramming on stem cells and lifespan, and to define an optimal treatment strategy to achieve rejuvenation without the risk of cancer induction.

Cellular senescence is characterized by a stable cell-cycle arrest of dysfunctional cells which also present with a senescence-associated secretory phenotype (SASP). Clearance of senescent cells with senolytics was shown to exert promising results on hematopoietic stem cells and muscle stem cells. Senescent cells form an inflamed niche that mirrors the inflammation associated with aging by arresting stem cell proliferation and regenerative potential. In young and aged mice, the reduction of senescent cells or of the inflammation associated with senescent cells accelerates tissue regeneration.

Cell polarization, defined as the uneven distribution of RNAs, proteins, organelles, and cytoplasm, occurs in many forms and the most widely known is the apical-basal polarity of epithelial cells. The capacity of establishing cell polarity, associated with the activity or the expression of specific polarity proteins, appears to be linked to aging of asymmetrically dividing cells such as stem cells. In the context of somatic stem cell rejuvenation, targeting cell polarity represents a potential strategy to improve tissue and organ regeneration. For example, Cdc42 is involved in the establishment of cell polarity in many cell types and its activity level increases over time, driving loss of polarity and aging in stem cells. Cdc42 activity can be efficiently targeted by using a specific small molecule inhibitor named CASIN (Cdc42 activity-specific inhibitor). CASIN treatment has been shown to rejuvenate different somatic stem cell types.