Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs with age, though insofar as the slow progress towards an official clinical definition is concerned, this only counts in the more advanced stages. We could do with less of that sort of thinking in medicine and research, as all age-related declines are a problem, and the earlier they can be addressed, the better. If a therapy addresses the root causes of an age-related condition, then it should be just as usefully applied every so often starting at 40, as a preventative treatment, as it would be starting at 70, in order to turn back much larger amounts of damage.
Sarcopenia is a great example of the way in which many areas of research into aging resemble the parable of the blind men and the elephant; every specialized research group looking at just one layer in a complex, interacting set of mechanisms and outcomes, and claiming their layer to be the most important. When reading the literature on sarcopenia, there are many theories and causes, most of which are backed by good evidence. Think of disruption of regenerative processes via chronic inflammation and stem cell decline, the role of cellular senescence in achieving that disruption, or, separately, neurological decline in the links between muscle and nervous system, reduced protein intake and lack of exercise in older individuals, and an age-related failure to process dietary amino acids.
As things stand, I think the stem cell researchers have a compelling last word with regard to the size of the contribution of declining stem cell activity on muscle atrophy in aging versus other possible causes. We then have to ask, however, why does muscle stem cell activity falter with age? What are the mechanisms driving that change? Research in recent years points to inflammatory signals as one of the ways in which regeneration and tissue maintenance are disrupted, and some portion of that inflammation arises from the signaling generated by growing numbers of senescent cells. Still, each of these named items is just one layer in a complex system - a system that is too complex to model well today. There are plenty of other causes of stem cell decline with evidence to support them. The true size of any specific contribution, the importance of any specific connection, will only be determined in the near future through some form of therapy that removes it. The best and fastest way to understand aging in detail is to fix the known forms of damage, one by one, and observe the results.
The paper here considers inflammation in sarcopenia, but not from the perspective of stem cell tissue maintenance. Rather, the authors focus on the way in which age-related increases in chronic inflammation might interfere with the protein synthesis needed to build muscle - which comes back around to the various studies suggesting that disruption in the processing of nutrients is a contributing cause of sarcopenia. Eventually everything is connected to everything else in aging and cellular biochemistry, given enough time to find the links. Advances in senolytic therapies to clear senescent cells and their inflammatory signaling, coupled with ways to reverse the age-related dysfunction of the immune system should in years ahead help to determine the degree to which sarcopenia is caused by inflammation.
One of the major problems in the aging population is a progressive loss in skeletal muscle mass, muscle strength, and/or functionality, described as age-related sarcopenia. Several strategies to attenuate the loss of muscle mass and other muscle impairments that comes with aging have been developed. However, none of these have been proven successful to fully reverse the muscle wasting condition. Given the high prevalence of sarcopenia in the aging population and the associated high health care costs, it is of importance to reveal and elucidate the working mechanisms which underlie muscle protein metabolism in the elderly, in order to optimize the classic interventions and/or to develop new ones.
Muscle protein metabolism is carefully regulated by counterbalanced fluctuations in muscle protein breakdown (MPB) and muscle protein synthesis (MPS). In the elderly, the balance between MPB and MPS seems to be disturbed, which progressively increases the loss of skeletal muscle mass. Many underlying factors such as hormonal changes, decreased activity, diminished nutrient intake, and neuronal changes were reported in the literature, but lately, the role of inflammation on the regulation of muscle protein metabolism has gained more and more interest among gerontologists.
Generally, aging is associated with a chronic state of slightly increased plasma levels of pro-inflammatory mediators, such as tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and C-reactive protein (CRP). This state is often referred to as a low-grade inflammation (LGI) and is, at least partly, the manifestation of increased numbers of cells leaving the cell cycle and entering the state of cellular senescence. Indeed, senescent cells acquire a Senescence-Associated Secretory Phenotype, which induces the production of pro-inflammatory cytokines (TNFα, IL-6 and an overactivation of NF-κB). Moreover, there is a growing interest in the association between the telomere/telomerase system and LGI, as cellular senescence can be triggered by critically short telomeres, representing irreparable DNA damage. Also, there are indications that LGI can directly cause telomere/telomerase dysfunction, enforcing the vicious LGI circle and stimulating an accelerated aging phenotype.
Although it has been suggested that inflammatory mediators affect muscle protein metabolism, it is not fully understood to what extent and through which signaling pathways they induce muscle wasting. Population-based data suggest that circulating concentrations of IL-6 and TNFα are significantly elevated in sarcopenic elderly and it was reported that higher IL-6 and CRP levels increase the risk of muscle strength loss. In a 10-year longitudinal study in community-dwelling elderly, plasma concentrations of TNFα, IL-6, and IL-1 were shown to be strong predictors of morbidity and mortality in older subjects. Furthermore, systemic inflammation was also reported as one of the primary mediators of skeletal muscle wasting and it was shown to accelerate aging in general. Without pronouncing on causality, these findings suggest that there is a link between inflammatory mediators and muscle mass and function.
A number of mechanisms have been shown to contribute to the etiology and/or progression of muscle wasting with advancing age. Somehow, many of these mechanisms interfere with inflammatory mediators. However, further research is required to determine through which mechanisms inflammation directly or indirectly affects MPB and MPS with aging. Classic interventions such as protein supplementation and resistance exercise are generally accepted to be the most appropriate to positively affect muscle protein metabolism in elderly. However, not all studies univocally support the effectiveness of these strategies for long-term treatment of age-related muscle wasting. Elderly, and very old or frail seniors in particular, might benefit from a strategy primarily focused on alleviating their muscle insensitivity to anabolic stimuli. In this regard, the treatment of LGI in these elderly might play an important role.