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Clearance of Senescent Cells as a Therapy for Age-Related Muscle Loss and Frailty


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#1 reason

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Posted 14 June 2018 - 09:12 PM


Today's open access review looks over the evidence for senescent cells to contribute to the age-related loss of muscle mass and strength, leading to sarcopenia and frailty. Regular readers will know that the research community has found many mechanisms that are arguably important contribution to the characteristic weakness of old age. This part of the field is rife with competing evidence for processes ranging from the comparatively mundane, such as an inadequate dietary intake of protein in older people, to the highly complex, such as the biochemical disarray that causes loss of neuromuscular junctions, and the interactions between those junctions and mechanisms of muscle tissue maintenance. The most compelling evidence points to stem cell dysfunction as the primary cause of loss of muscle and strength with age. But then we might well ask which of the fundamental causes of aging produces that stem cell dysfunction?

The review here argues for cellular senescence to be an important cause. Senescent cells accumulate over time, a tiny fraction of the countless cells that become senescent every day managing to linger rather than self-destruct. The immune system clears out near all of those, but the immune system falters with age. Cancer is an age-related disease in large part because of this loss of capability in the portions of the immune system responsible for destroying errant cells, and the accumulation of senescent cells is no doubt in the same boat. Yet even in very old tissues, only a small percentage of cells are senescent. The harm they cause is not direct, but rather results from the potent mix of signals that they generate. Those signals produce chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse.

Just looking at chronic inflammation, it is known that this state can disrupt the normal processes of tissue maintenance and regeneration. But there are many other mechanisms worth surveying when it comes to the ways in which cellular senescence might be acting to suppress the activity of stem cell populations, thus leading to atrophy and loss of function in tissues such as skeletal muscle. What if these senescent cells could be removed, however? Might we expect some degree of rejuvenation of stem cell activity? That doesn't seem an unreasonable goal, based on the evidence to date. Senolytic therapies capable of clearing a fraction of senescent cells already exist, albeit not packaged up for the mass market, and not yet run through rigorous human trials. More effective therapies are entering the regulatory pipeline, under development in a number of young companies, and will arrive in the clinic over the years ahead.

Musculoskeletal senescence: a moving target ready to be eliminated

Aged individuals can deteriorate exceptionally fast after the onset of complications affecting the musculoskeletal system. Tissue erosion due to life-long mechanical and biological stress can ultimately result in pathologies such as osteoporosis, sarcopenia, and osteoarthritis, and contribute to frailty. While not all elderly people develop the same age-related diseases, virtually everyone will experience musculoskeletal complications sooner or later. To extend, and possibly even restore, healthy life expectancy in old age, it is essential to understand the cellular changes underlying musculoskeletal decline.

Tissue regeneration by stem-cell differentiation is critical in overcoming the relentless day-by-day damage to the musculoskeletal system. In young tissues, differentiation proceeds without much hindrance unless one exercises excessively or suffers undue levels of stress. However, during aging, the number and function of adult stem cells declines. For example, Pax7-expressing satellite stem cells, can replace damaged muscle fibers. Removing Pax7-positive cells from mice impairs muscle regeneration after injury, whereas increased availability of these cells enhances muscle repair.

In addition to cell-intrinsic regulation, muscle stem cell regenerative capacity also depends intimately on the microenvironment. During aging, the levels of inflammation chronically increase, an affect known as inflammaging. Evidence for this is provided by studies showing that muscle stem cells (satellite cells) from aged mice become more fibrogenic, a conversion mediated by factors from the aged systemic environment. In contrast, frailty is reduced by the JAK/STAT inhibitor Ruxolitinib, which reduces inflammation in naturally aged mice. Stem-cell impairing cues do not necessarily have to come from local sources but can travel over a distance. Therefore, there is a great interest in developing methods to interfere with the age-associated pro-inflammatory signaling profile. The question is how? To address this question, cellular senescence has recently gained attention as a potential candidate for intervention.

As we age, each cell in our body accumulates damage. Earlier in life, this damage is usually faithfully repaired, but over time more and more damage gets left behind. This can trigger a molecular chain of events, resulting in the entry of cells into a permanent state of cell-cycle arrest, called cellular senescence. Senescence can be invoked in healthy cells that experience a chronic damage response, either involving direct DNA damage or events that mimic the molecular response, such as telomere shortening or oncogenic mutations. As a consequence, these cells undergo an irreversible cell cycle arrest, effectively limiting the damage. So far, so good, except that senescent cells secrete a broad range of growth factors, pro-inflammatory proteins, and matrix proteinases that alter the microenvironment: the Senescence-Associated Secretory Phenotype (SASP).

Senescent cells persist for prolonged periods of time and eventually accumulate during aging. This also means there is a gradual and, importantly, ever-present build-up of deleterious molecules. Thus, senescence can have continuous detrimental effects on tissue homeostasis during aging. That senescent cells are a direct cause of aging was proven beyond a doubt in studies in which senescent cells were genetically or pharmacologically removed. In these studies, both rapidly and naturally aged mice maintained healthspan for much longer, or even showed signs of aging reversal.

Factors secreted by senescent cells can induce pluripotency in vivo. As such, these can impair normal stem cell function by forcing a constant state of reprogramming, something we dubbed a `senescence - stem lock'. Age-associated inflammation may thus deregulate normal stem cell function at different levels, for instance by preventing stem cells from producing differentiated daughter cells. Due to the constant secretion of SASP factors, senescent cells could thus impair local and distant stem cell function and differentiation in times of need. Here, we will highlight the interplay between senescence, the SASP and stemness in the individual musculoskeletal compartments: muscle, bone, and cartilage.


View the full article at FightAging

#2 Rocket

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Posted 15 June 2018 - 12:40 AM

It seems to me these studies don't translate well into humans. There are a lot of people taking part in the FOXO4 peptide trial and the reports are less than stellar...
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