Fight Aging!

As a topic for aging research, cellular senescence passed its tipping point a few years ago. Prior to that growth of interest and attention it was a struggle to raise funding for this area of work, and thus it didn't matter how compelling the evidence was for its involvement in the processes of aging. Researchers follow the course that ensures funding, not the course that ensures progress. Sometimes we are fortunate and those two streams overlap, but it is more often the case that great efforts of persuasion and philanthropy are required to shift the scientific mainstream onto the right track, such as that undertaken by the Methuselah Foundation and SENS Research Foundation over the past fifteen years.

Never for one moment think that scientific research at the large scale progresses rationally towards optimal outcomes: it is just as prone to human whim and fallibility as all other fields of research; those involved are just as likely to ignore the high road in favor of the low road simply because the low road is easier. Fortunately for all of us, when it comes to senescent cells and their role as a root cause of aging, the fight to make this a major topic of research is done and finished, the point made, the funding in full flow, and now everyone is working to incorporate cellular senescence into their portfolio - doing what could have been accomplished ten to fifteen years ago, had there been the will and the interest at that time.

A great deal of attention of late has been directed towards the role of cellular senescence in the age-related decline of muscle regeneration. The stem cells responsible for maintaining muscle tissue are one of the most studied stem cell populations, and thus a sizable fraction of new discoveries in regeneration and aging take place in this context. Do growing numbers of senescent cells produce signaling that causes stem cell populations to become less active, or do the stem cell and related populations involved in muscle regeneration fall into a senescent state themselves? These and many other questions remain to be firmly answered, but now that senescent cells can be selectively destroyed, those answers should be arriving more rapidly than would otherwise be the case.

New Insights on Triggering Muscle Formation

Researchers have identified a previously unrecognized step in stem cell-mediated muscle regeneration. The study provides new insights on the molecular mechanisms that impair muscle stem cells (MuSCs) during the age-associated decline in muscle function that typically occurs in geriatric individuals. It also provides further insight into the connection between accelerated MuSC aging and muscular dystrophies. "In adult skeletal muscle, the process of generating muscle - myogenesis - depends on activating MuSCs that are in a resting, or quiescent, state. As we age, our MuSCs transition to a permanently inactive state called senescence, from which they can't be 'woken up' to form new muscle fibers. If we could encourage senescent MuSCs to start replicating and advance through myogenesis - perhaps through pharmacological interventions - we may have a way to help build muscle in patients that need it."

The goal of the study was to define the molecular determinants that lead to irreversible MuSC senescence. Using a combination of a mouse model and human fibroblasts, the team found that the reason old MuSCs can't be activated to generate muscle cells is that they spontaneously activate a DNA damage response (DDR) even in the absence of exposure to exogenous genotoxic agents. This senescence-associated DDR chronically turns on the machinery needed to repair breaks and errors in DNA, and activate cell cycle checkpoints, which inhibit cells from dividing. "In our study, we found that the senescence-associated DDR prevents MuSCs from differentiating by disabling MyoD-mediated activation of the muscle gene program. We also learned that a prerequisite for activating the muscle gene program is progression into the cell cycle, a process that is irreversibly inhibited in senescent cells. We did identify experimental strategies to get senescent cells to move through the cell cycle and activate myogenesis, which is a promising result. However, we also discovered that enforcing old MuSCs to form new muscles might lead to the formation of myofibers with nuclear abnormalities resulting from genomic alterations generated during aging."

"Given the tremendous impact that decline in muscle function has on aging and lifespan, research that elucidates pathways and networks that contribute to the progressive impairment of MuSCs - such as that reported here - may lead to targeted pharmacological interventions that improve human health. However, the findings from this study should warn against overenthusiasm for strategies aimed at rejuvenating muscle of elderly individuals by enforcing the regeneration process, as they might carry a sort of trade-off at the expense of the genomic and possibly functional integrity of the newly formed muscles."

DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation

The molecular determinants of muscle progenitor impairment to regenerate aged muscles are currently unclear. We show that, in a mouse model of replicative senescence, decline in muscle satellite cell-mediated regeneration coincides with activation of DNA damage response (DDR) and impaired ability to differentiate into myotubes. Inhibition of DDR restored satellite cell differentiation ability. Moreover, in replicative human senescent fibroblasts, DDR precluded MYOD-mediated activation of the myogenic program.

A DDR-resistant MYOD mutant could overcome this barrier by resuming cell cycle progression. Likewise, DDR inhibition could also restore MYOD's ability to activate the myogenic program in human senescent fibroblasts. Of note, we found that cell cycle progression is necessary for the DDR-resistant MYOD mutant to reverse senescence-mediated inhibition of the myogenic program. These data provide the first evidence of DDR-mediated functional antagonism between senescence and MYOD-activated gene expression and indicate a previously unrecognized requirement of cell cycle progression for the activation of the myogenic program.