Which Approach to Choose to Counteract Musculoskeletal Aging? A Comprehensive Review on the Multiple Effects of Exercise

Abstract

Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging.

Keywords: aging; musculoskeletal system; physical exercise; physiology; prevention; senescence; senotherapeutic.

Figure 1

Chemical structure of the main natural compounds with senotherapeutic properties. (a) Resveratrol: polyphenolic phytoalexin. (b) Rapamycin: macrocyclic lactone. (c) Quercetin: flavonoid. (d) Curcumin: polyphenol. (e) Vitamin E: fat-soluble micronutrient composed of tocopherols and tocotrienols. (f) Genistein: isoflavone. (g) Fisetin: flavonol. (h) Epicatechin: flavonol. Images acquisition from PubChem.

Figure 2

Chemical structure of the main synthetic compounds with senotherapeutic properties. (a) Dasatinib. (b) Navitoclax. (c) UBX0101. (d) Panobinostat. (e) Metformin. Images acquisition from PubChem.

Figure 3

Potential strategies to counteract musculoskeletal aging. Physical exercise is an effective intervention for preserving musculoskeletal health during aging, thanks to its ability to modulate numerous pathways involved in cellular senescence, including phosphoinositide 3-kinase (PI3K)/Akt, mechanistic target of rapamycin (mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/estrogen-related receptor alpha (ERRα). In addition, physical exercise can modulate the expression of cell cycle regulators, including p16, p21, and p53, as well as anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL). Finally, physical exercise is known to regulate the expression of factors associated with oxidative stress response and energy metabolism, such as nuclear factor erythroid 2-related factor 2 (NRF2), AMP-activated protein kinase (AMPK), sirtuins, and forkhead box O (FoxO). These molecular pathways are also targets of action for numerous senotherapeutics, including natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin, and synthetic compounds, including dasatinib, navitoclax, UBX0101, panobinostat, and metformin (up arrow: increase, down arrow: decrease).