Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?

During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.

Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

The study of the extreme limits of human lifespan may allow a better understanding of how human beings can escape, delay, or survive the most frequent age-related causes of morbidity, a peculiarity shown by long-living individuals. Longevity is a complex trait in which genetics, environment, and stochasticity concur to determine the chance to reach 100 or more years of age [1]. Because of its impact on human metabolism and immunology, the gut microbiome has been proposed as a possible determinant of healthy aging [2, 3]. Indeed, the preservation of host-microbes homeostasis can counteract inflammaging [4], intestinal permeability [5], and decline in bone and cognitive health [6, 7]. Aiming at deepening our knowledge on the relationship between the gut microbiota and a long-living host, we provide for the first time the phylogenetic microbiota analysis of semi-supercentenarians, i.e., 105-109 years old, in comparison to adults, elderly, and centenarians, thus reconstructing the longest available human microbiota trajectory along aging. We highlighted the presence of a core microbiota of highly occurring, symbiotic bacterial taxa (mostly belonging to the dominant Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families), with a cumulative abundance decreasing along with age. Aging is characterized by an increasing abundance of subdominant species, as well as a rearrangement in their co-occurrence network. These features are maintained in longevity and extreme longevity, but peculiarities emerged, especially in semi-supercentenarians, describing changes that, even accommodating opportunistic and allochthonous bacteria, might possibly support health maintenance during aging, such as an enrichment and/or higher prevalence of health-associated groups (e.g., Akkermansia, Bifidobacterium, and Christensenellaceae).