Signs of Cellular Senescence in Aged Bone Marrow, Contributing to Impaired Generation of Immune Cells

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.

Comments

I would prefer to wait 10 years, but, given that I will be 60 at years end, I plan to peruse the newly gotten data over the next year, and dive in. I think for younger people, they ought to wait 5 to 10 years just so the researchers can find the optimized treatment for this, IMO.

Posted by: Robert at March 13th, 2019 5:30 PM

@Robert
I think it depends a lot on individual circumstance. If you are in good health you can wait. If you had a high pro aging burden then your can try earlier. Fisetin seems pretty harmless, while Dasatinib is much nastier.

If you are younger you can tolerate much higher dose of some aggressive senolitics. But then if you are in a good help you will derive much less benefits. We also don't really know whether taking senolytics when young actually brings any benefits , even marginal ones...

Now seems that SC are compounding and aggravating almost any chronic condition. And after 40 it is very common to have at least one. Go figure..

Posted by: Cuberat at March 13th, 2019 7:09 PM

I'll wait too, and I'm 45. But probably I'll invest in a senolytic company when I have more money. I prefer that than spending in medical tourism or self-experiments.

Posted by: Antonio at March 14th, 2019 3:38 AM

Thanks for your input Cuberat.

I am hoping that info gathered this year will indicate when is the youngest age recommended to start the senolytic treatment. If they can safety package the Fisetin in a pill w/o eating a huge amount of strawberries, that would be a huge win, IMO.

I am waiting with baited breath for results to come in:)

Posted by: Robert at March 14th, 2019 12:24 PM

You can get fisetin in a capsule. Reading the literature on this I worked it out at about 10 x 100mg capsules per day over 4 to 5 days (with oil). Whether the effect I got was placebo or not I don't know, because I've also been fasting and taking other stuff, but I felt crappy while taking it then, after refeeding and recovery, I lost the need for a daytime nap and seemed to have more energy. But again, maybe placebo.

Posted by: Neal Asher at March 18th, 2019 6:42 AM

Thanks Neal,

Are your fesetin from strawberries, and if so, is it organic? As you probable know, strawberries are the crops with most pesticides used unless they are organic.

Posted by: Robert at March 18th, 2019 8:45 PM

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