The Potential Influence of Gut Microbes on the Progression of Sarcopenia

Sarcopenia is the name given to the characteristic age-related loss of muscle mass and strength that affects every older adult, and eventually significantly contributes to outright frailty. For the past decade or more US researchers have been agitating to have sarcopenia officially defined as a medical condition, with no success yet. Indeed, this is a poster child for one of the ways in which the stifling effect of heavy regulation emerges in practice. For so long as the FDA doesn't consider sarcopenia a disease, then it becomes that much more challenging to raise funding for research and development of potential therapies; large commercial ventures won't consider it seriously, and in turn that lack of interest spreads back into earlier stages of research funding, for-profit and non-profit. The whole field slows down because someone's arbitrary boxes are not being checked.

There are many potential contributing causes to sarcopenia, all of which sound at least somewhat plausible and arrive accompanied by a fair amount of supporting evidence. Lower protein intake in older adults; defective processing of the amino acid leucine; sedentary behavior; chronic inflammation that disrupts the signaling and cell behavior needed for normal tissue maintenance; age-related decline in stem cell activity; infiltration of muscles by fat tissue; changes in mitochondrial dynamics that reduce energy output; blood vessel decline that reduces oxygenation; and loss of function neuromuscular junctions, to pick a few examples. The latest animal studies point firmly to stem cell decline as the primary cause, but there is a still quite a weight of research, collectively, for all of the other potential mechanisms. As in so many other areas of aging, the fastest path to assigning relative importance is probably to start fixing causes one by one and see what happens as a result.

In the paper noted here, researchers consider age-related changes in the gut microbiome as a way to make more sense of what has been reported of nutritional contributions to sarcopenia. In recent years the work of an increasing number of research groups has suggested that the bacteria of the gut are influential on natural variations in the pace of aging, perhaps to a degree that is in the same ballpark as exercise. Further, gut bacteria account for one portion of the many and varied mechanisms by which lowered calorie intake slows aging. The more compelling demonstrations are those in which transfer of gut bacteria from young to old animals extends life. Whether anything of significance to medicine arises from this is another matter entirely, however: consider how much time and effort has been spent on trying to reverse engineer exercise and calorie restriction, with little to show for it to date. The gut microbiome and its interaction with our biology is at least as complex, and possibly more so. The size of the potential benefits are just not that large in the grand scheme of things - perhaps a few additional years of life. There are better opportunities to chase with that same effort and funding, such as any of those in the SENS rejuvenation research portfolio.

Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut-Muscle Axis?

Sarcopenia is a geriatric syndrome with a high prevalence in older individuals; its presence is estimated in up to 35% of hospital wards. Elderly individuals generally experience a decline of nutrient and energy intake with increasing age. This phenomenon is generally due to age-related loss of appetite, the so-called "anorexia of aging", whose physiopathology is only partly understood. It may also depend on increased energy requirements due to acute or chronic inflammation, leading to "disease-related malnutrition". Malnutrition and sarcopenia often overlap in older patients, so that one of the mainstays of sarcopenia prevention and treatment is promoting adequate nutrition. The prescription of adequate intakes of proteins, vitamin D, antioxidant nutrients, and long-chain polyunsaturated fatty acids has been particularly emphasized in this field, since these nutrients are able to counteract anabolic resistance, promote protein synthesis, and modulate inflammation, thereby preventing its detrimental consequences on muscle cells.

The human gut microbiota is composed of as much as 1014 bacteria, viruses, fungi, protozoa, and Archaea, with a gene pool 150 times larger than that of the host. It establishes a symbiotic relationship with the host, whereby individual environmental and genetic factors can shape its composition, while the host physiology is influenced and gets adapted to its presence. In healthy individuals, the gut microbiome generally includes between 1100 and 2000 bacterial taxa, most of which cannot be cultivated with traditional microbiological techniques.

Geographical location and diet are the major environmental factors explaining the interindividual differences in healthy gut microbiota composition. After the age of 65, gut microbiota resilience is generally reduced, so that its overall composition is more vulnerable to lifestyle changes, drug treatments such as antibiotics, and disease. As a result, species richness (i.e., the number of taxa that metagenomic analyses are able to identify) is reduced, and interindividual variability is enhanced. A lower number of species, decrease in the representation of taxa with purported health-promoting activity, and expansion of Anaerotruncus, Desulfovibrio, Coprobacillus and Gram-negative opportunistic pathogens are the most important changes that have been demonstrated in different clinical settings. These distinctive features of older persons' gut microbiome allow hypothesizing its involvement in the aging process with multiple mechanisms.

In a pioneering study on the ELDERMET cohort, it was demonstrated that the species richness of the fecal microbiota of older subjects is inversely related to physical performance. A secondary analysis of the same cohort has recently revealed that, in community dwellers, the presence of frailty, as measured through the Barthel Index (BI), is associated with a gut microbiome profile similar to that typical of nursing-home residents, with an increased representation of Anaerotruncus, Desulfovibrio, and Coprobacillus. These results are not merely speculative; they have important clinical correlates. For example, gut microbiota dysbiosis can be associated with a reduced survival in older individuals with frailty or disability. Moreover, the over-representation of opportunistic pathogens in the gut microbiota of frail multimorbid older patients may also increase the risk of developing infections.

However, these studies do not establish any cause-effect relationship between gut microbiota dysbiosis and physical frailty, due to their cross-sectional design. Several compounds produced or modified by the gut microbiota can enter systemic circulation and ultimately influence skeletal muscle cells. For example, a healthy gut microbiota is able to produce significant amounts of folate and vitamin B12, which may improve muscle anabolism. The most studied putative mediators of the effect of gut microbiota on skeletal muscle function are short chain fatty acids (SFCAs). These substances are generally derived from the bacterial metabolism of nutrients, such as proteins, which are introduced with diet. Their main host targets are skeletal muscle mitochondria.

The only intervention study carried out on older patients and targeted at exploring the effects of gut microbiota modifications on skeletal muscle outcomes involved the administration of prebiotics, i.e., substances promoting the overexpression of beneficial bacteria. In a randomized controlled trial, researchers enrolled 60 older patients who received treatment with a prebiotic formulation including fructooligosaccharides and inulin versus placebo for 13 weeks. Surprisingly, the treatment group experienced improvement in two outcomes of muscle function: exhaustion and handgrip strength. Thus, these data support the hypothesis of a modulation of muscle function by gut microbiota. Unfortunately, no other studies have explored this field to date.

The current state-of-the-art literature supports the hypothesis that gut microbiota may be involved in the onset and clinical course of sarcopenia. Since nutrition is one of the main determinants of gut microbiota composition, and is also involved in the pathogenesis of sarcopenia, the gut microbiota may be at the physiopathological cross-road between these two elements. Some key microbial taxa may have a relevant role in determining muscle structure and function by producing metabolic mediators that influence the host physiology after intestinal mucosa absorption. Glycine betaine, tryptophan, biliary acids, and SCFA, namely butyrate, are the most promising of these putative mediators.