Fight Aging!

The accumulation of lingering senescence cells with age is apparently there to be discovered in every tissue in the body, and researchers are gathering a great deal of data now that it is generally accepted that these errant cells are one of the causes of aging. The overt signs of cellular senescence in a tissue are much the same throughout the body, even if there may well be significantly different classes of senescent cell still to be categorized. All senescent cells examined to date generate inflammatory, harmful secreted molecules that rouse the immune system, disrupt surrounding cell activities, destructively remodel the extracellular matrix, and more. All of this is a necessary part of regeneration when it takes place over the short term, but when the secretions of senescent cells continue without resolution, over years, the diseases, declines, and chronic inflammation of aging emerge.

In today's open access paper, researchers identify signs of cellular senescence in bone marrow cell populations as a contributing factor to the age-related decline of hematopoietic activity, the very necessary creation of immune and blood cells by hematopoietic stem cells. A reduced supply of new immune cells is one of the major contributing causes of age-related immunosenescence, the faltering of the immune system. The immune system is so fundamental to health that its fall into chronic inflammation and ineffectiveness may be a primary driver of human late-life mortality. Certainly, there is a wide range of evidence linking aspects of immune function with mortality in human cohorts.

What do we do about cellular senescence? We deploy senolytic therapies systemically throughout the body, targeting senescent cells for destruction by triggering apoptosis. The initial set of senolytic compounds used in research and early testing seem moderately effective in mice, clearing up to half of senescent cells from some tissues, and human data is starting to arrive this year. These compounds are cheap and easily obtained by those who don't wish to wait five to ten years for an expensive (and only maybe improved) version to emerge from the regulatory pathway of clinical trials. The research community will be kept quite busy in the years ahead by assessing cellular senescence, and then the removal of senescent cells, in the context of each and every decline of aging. But anyone willing to accept the risks of self-experimentation, after reading through the existing evidence and making an informed decision, can always choose to forge ahead today and try for themselves, to see what happens to their own age-related conditions.

An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program

Hematopoietic stem and progenitor cells (HSPC) can self-renew and differentiate into all blood components thus serving as a reservoir for mature blood cells throughout life. However, as we age, HSPC functionality is impaired with cells displaying a reduced capacity to maintain tissue homeostasis. Hematopoietic stem and progenitor cells reside in the bone marrow (BM) niche, and their function is supported by a variety of both hematopoietic and nonhematopoietic cell types, such as osteoblasts, adipocytes, endothelial, and mesenchymal stromal cells (MSC). Several studies highlighted the key role of MSC in regulating HSPC fate and promoting engraftment of the rare and more primitive hematopoietic stem cells (HSC). Indeed, changes in the cellular composition of the HSC niche during aging contribute to hematologic decline and involve decreased bone formation, enhanced adipogenesis, increased BM inflammation, and altered HSPC-MSC crosstalk.

Senescent cells accumulate during aging and contribute to tissue dysfunction and impaired tissue regeneration. Senescence is also characterized by increased SA-β-Gal activity, persistent DNA damage repair activation, and telomeric attrition. Moreover, senescent cells exhibit transcriptional activation of a senescent-associated secretory inflammatory phenotype collectively known as SASP. The robust secretion of SASP chemokines/cytokines triggers an inflammatory response that could reinforce senescence in a cell-autonomous fashion and be transferred to surrounding cells through paracrine mechanisms, to amplify the senescence response.

To date, the activation of a senescence program in human aged MSC and the interplay between aged MSC and HSPC remain to be elucidated. In this study, we successfully established human BM-derived MSC from young and elderly healthy donors. We investigated the effects of chronological age on MSC properties and found that MSC derived from aged healthy subjects show senescence-like features comprising an enlarged morphology, reduced proliferation capacity, delayed cell cycle progression, and increased levels of SA-β-Gal and lipofuscin. Importantly, we found that aged MSC activate a SASP-like program that contributes in a non cell autonomous manner to impair young HSPC clonogenicity by mediating an inflammatory state in HSPC.

Over the past decade, a growing body of evidence revealed that inflammatory stimuli alter HSPC fate and functionality by affecting HSPC proliferation/quiescence status, differentiation potential, or HSPC-niche interactions. In particular, it has been reported that chronic inflammation drives HSPC myeloid skewing and leads to HSPC exhaustion during aging. Our data indicate that the secretome of aged MSC may as well contribute to boost inflammation in HSPC in a paracrine fashion. However, further investigations are needed to dissect the role of individual SASP factors secreted by aged MSC on HSPC biology and to determine whether chronic exposure of young HSPC to MSC-derived inflammatory molecules may induce paracrine senescence in HSPC as previously described in other settings.