Cellular Senescence and Stem Cell Aging

In recent years, researchers have provided evidence to suggest that cellular senescence mechanisms are partly involved in the decline of stem cell activity in aging. It is an open question as to how this interacts with other signaling mechanisms also recently shown to influence the suppression of stem cell tissue maintenance. This is one part of a larger discussion over the degree to which loss of stem cell activity is due to internal factors localized within the stem cell populations, such as cellular damage, or external factors such as changes in cell signaling systems that are a reaction to more widespread damage in tissues:

Regeneration of skeletal muscle relies on a population of quiescent stem cells (satellite cells) and is impaired in very old (geriatric) individuals undergoing sarcopenia. Stem cell function is essential for organismal homeostasis, providing a renewable source of cells to repair damaged tissues. In adult organisms, age-dependent loss-of-function of tissue-specific stem cells is causally related with a decline in regenerative potential. Although environmental manipulations have shown good promise in the reversal of these conditions, recently we demonstrated that muscle stem cell aging is, in fact, a progressive process that results in persistent and irreversible changes in stem cell intrinsic properties.

Global gene expression analyses uncovered an induction of p16INK4a in satellite cells of physiologically aged geriatric and progeric mice that inhibits satellite cell-dependent muscle regeneration. Aged satellite cells lose the repression of the INK4a locus, which switches stem cell reversible quiescence into a pre-senescent state; upon regenerative or proliferative pressure, these cells undergo accelerated senescence (geroconversion), through Rb-mediated repression of E2F target genes. p16INK4a silencing rejuvenated satellite cells, restoring regeneration in geriatric and progeric muscles. Thus, p16INK4a/Rb-driven stem cell senescence is causally implicated in the intrinsic defective regeneration of sarcopenic muscle. Here we discuss on how cellular senescence may be a common mechanism of stem cell aging at the organism level and show that induction of p16INK4a in young muscle stem cells through deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype.

Link: http://dx.doi.org/10.4161/15384101.2014.965072

Comments

It is the Stem cell niche aged phenotype that dictates if the Stem cell is active or dormant. Check out Irina Conboys beyond parabiosis video that talks about this. If the niche can be rejuvenated it can return Stem cells into service and that is something I understand she is working on. Factors in the blood almost certainly dictate the stem cell niche age so if you can work out what that is (or emulate or use young plasma) it may reverse the phenotype as seen in the various animal experiments going back years eg, Rando, Villeda, Katcher, Conboy, Wagers, Wyss-Corey etc...

Posted by: Steve H at May 28th, 2015 8:00 AM

@Steve - It is probably easier just to remove the senescent cells.

Posted by: Jim at May 28th, 2015 9:00 AM

Yes Jim but what about the dormant Quiescent cells? These can be woken up and returned to work if the niche environment is de-aged.

Posted by: Steve H at May 28th, 2015 10:22 AM

I still suspect it will be easier to remove senescent cells/damaged mitochondria/cross links/inter&intra cellular aggregates than trying to modify potentially hundreds of downstream signaling protein and molecule changes.

Also consider that mice have near miraculous regenerative capabilities compared to humans. A single factor that has a positive effect in them may not translate to humans.

Posted by: Jim at May 28th, 2015 10:52 AM

So, actually, Steve and Jim: you're both right ;) . Aging is not an unitary process: it is the accumulation over the lifetime of multiple forms of cellular and molecular damage. On the one hand, some muscle cells — including, it appears, some cells that would otherwise be satellite cells (skeletal muscle stem cells) — become senescent over the course of life, at least in mice (no studies in humans of which I'm aware). We know that these cells exert deleterious effects just like other senescent cells: both Kirkland's earlier study in the BubR1-hypotrophic mice and the newer study in mice with irradiated hindlegs subsequently administered "senolytics" found that clearing these cells improved muscle quality and exercise performance on the treadmill test. On the other hand, it is also true that (of course) there remain functional and apparently largely undamaged satellite cells in aging tissues that none the less remain quiescent in the face of injury due to the baleful influence of the aging systemic milieu, and restoration of a more youthful systemic milieu via parabiosis restores more youthful regenerative response.

Of course, a key point is here is that the way you restore a youthful systemic environment without what Jim rightly characterizes as an endless and fraught tweaking of perhaps hundreds of dynamically-regulated, transient, soluble signaling factors is to remove, repair, replace, and render harmless the cellular and molecular damage of aging that makes the aged systemic milieu suppress satellite cell function in the first place. Indeed, it's likely that the rejuvenating effects of clearing senescent cells from aging muscle observed in the op cit studies is, exactly, due to a partial restoration of a more youthful systemic milieu, by abrogating the SASP locally. Obviation of deletion mutations in muscle fibers (one of the tissues in which their accumulation is most evident with age) should go even further, by eliminating a local source of oxidative stress. We can also anticipate that application of any number of other rejuvenation biotechnologies will also contribute to varying degrees to local and wider systemic re-setting of the systemic milieu to the youthful norm, whether or not we can as yet predict their individual effects on that milieu.

Posted by: Michael at May 29th, 2015 12:48 PM

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