Fight Aging!

Senescent cells accumulate with age, and contribute to the dysfunction of aging via their inflammatory secretions. A cell becomes senescent in response to reaching the Hayflick limit on replication, or in response to damage or stress. In the normal course of events, a senescent cell ceases replication, and this is an irreversible change. A few approaches have been demonstrated to reverse this aspect of the senescent state. The question is whether it is a good idea to do so. For example, senescent cells accumulate DNA damage on entry to the senescent state. Some senescent cells are senescent for good reason, such as potentially cancerous DNA damage. It has been thought that allowing these cells to replicate again is just asking for trouble.

Still, some researchers have explored reversal of senescence. In today's open access paper, quite compelling evidence is provided for reversal of senescence to be a good thing: the mice involved in the study live longer, show improved function, and suffer no increase in cancer incidence. This is quite fascinating, and certainly not what one might expect. One way to look at this is to theorize that most senescent cells present in an aged animal are not in fact senescent for any good reason, and that much of their DNA damage is innocuous or can be repaired on exiting the senescent state. Possibly, as seems to be the case for telomerase gene therapy, increased cancer risk due to enabling the activity of problem cells is outweighed by improvements in immune function and surveillance of those problem cells.

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells

Senescent cells (SnCs) accumulate during aging and secrete the senescence-associated secretory phenotype (SASP), promoting secondary senescence and disrupting normal tissue functions. Consequently, targeting SnCs has emerged as a promising strategy to prolong healthspan and delay the onset of age-related diseases. Therapies targeting SnCs are broadly divided into two major categories: elimination of SnCs (senolytic) and suppression of pathological SASP signaling (senomorphic). These strategies have shown therapeutic benefits in aging and related diseases, including extending lifespan, alleviating inflammation, and improving cognition. However, they also have certain limitations. While the senolytic strategy may effectively eliminate SnCs when scarce, the prevalence of SnCs in tissues increases as individuals age. Eliminating them may result in considerable tissue damage and compromise normal organ function. Moreover, although SASP suppression has rejuvenating effects, it can impede immune surveillance of pathogens and cancer cells. Developing new rejuvenation strategies that target SnCs is crucial to address these challenges.

In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs in vitro. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors Cdkn1a and Ccng2. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs in vivo, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.