Aging, obesity, sarcopenia and the effect of diet and exercise intervention

Abstract

The number of adults 65 years and older is increasing worldwide and will represent the 20% of the population by 2030. Half of them will suffer from obesity. The decline in muscle mass and strength, known as sarcopenia, is very common among older adults with obesity (sarcopenic obesity). Sarcopenic obesity is strongly associated with frailty, cardiometabolic dysfunction, physical disability, and mortality. Increasing efforts have been hence made to identify effective strategies able to promote healthy aging and curb the obesity pandemic. Among these, lifestyle interventions consisting of diet and exercise protocols have been extensively explored. Importantly, diet-induced weight loss is associated with fat, muscle, and bone mass losses, and may further exacerbate age-related sarcopenia and frailty outcomes in older adults. Successful approaches to induce fat mass loss while preserving lean and bone mass are critical to reduce the aging- and obesity-related physical and metabolic complications and at the same time ameliorate frailty. In this review article, we discuss the most recent evidence on the age-related alterations in adipose tissue and muscle health and on the effect of calorie restriction and exercise approaches for older adults with obesity and sarcopenia, emphasizing the existing gaps in the literature that need further investigation.

Keywords: Adipose tissue; Diet; Elderly; Exercise; Frailty; Lifestyle interventions; Sarcopenia; Skeletal muscle.

Figure 1:. Skeletal muscle and adipose tissue in older adults suffering from obesity by MRI.

A. Abdominal MRI of an older adult with obesity; arrows indicate SAT: subcutaneous adipose tissue and VAT: visceral adipose tissue; L: liver; k: kidney. B. Thigh MRI of an older adult with obesity; arrows indicate intermuscular adipose tissue (IMAT). Thigh MRI of an older adult with obesity before (C) and after (D) diet-induced weight loss plus combined aerobic and resistance exercise training (6 months intervention). Total mass, fat mass and lean mass data refer to whole body composition assessed by dual energy x-ray absorptiometry.

Figure 2:. Adipose tissue and muscle dysfunction in obesity and aging

A and B (hematoxylin staining): light microscopy of visceral adipose tissue belonging to a 71-year-old woman with central obesity. A: elevated infiltration of inflammatory cells (partly indicated by arrowheads) often forming crown-like structures surrounding adipocytes; (20x magnification). B: squared area indicates an example of crown-like structure (40x magnification). C and D (hematoxylin and eosin staining): fat infiltration within the erector spinae muscle of an older adult; adipocytes infiltration indicated in the squared area in C (10x magnification); D (40x magnification) shows adipocytes infiltration within atrophic fibers (arrowhead) in the same subject.

Figure 3:. Schematic representation of skeletal muscle alterations occurring with obesity and aging.

Fat infiltration and inflammation; anomalies in protein quality control mechanisms (e.g., autophagy and ubiquitin proteosome system function); reduced muscle protein synthesis in response to anabolic stimuli (i.e., exercise, food ingestion); reduced myogenesis and muscle regeneration capacity; alterations in mitochondrial function and dynamics (e.g., mitophagy, fission and fusion) and in neuromuscular junction efficiency. All these processes are strictly associated with reduced muscle quality and strength, ultimately resulting in muscle wasting, disability and impaired physical function (frailty).

Figure 4:. Schematic representation of the Lifestyle Intervention Trial in Elderly Obese (LITOE).

A total of 160 of older men and women (≥65 years of age) with obesity (BMI≥30 kg/m²) and frailty were randomized to diet-induced weight loss plus either aerobic, resistance or the combination of both exercise modalities for 6 months. A fourth set of subjects was included in the control group who did not undergo diet or exercise intervention but received educational classes on a healthy lifestyle. Forty-seven subjects from the LITOE trial participated in the muscle sub-study and underwent vastus lateralis biopsies to investigate muscle protein synthesis response to anabolic stimuli (meal ingestion) and myocellular quality. The study was completed at the end of 2018 (LITOE ClinicalTrials.gov number, NCT01065636).

Figure 5:. Pathways involved in the age- and obesity- related muscle dysfunction, affected by weight loss plus aerobic and resistance exercise.

Aging and obesity are characterized by muscle lipids infiltration and a state of chronic, low-grade inflammation, e.g., higher circulating IL-6 and TNF-α. Inflammation contributes to muscle wasting impairing i) the anabolic action of the IGF1-mTOR pathway and muscle protein synthesis response to anabolic stimuli (already lower in older adults) and ii) promoting the expression of atrogenes such as regulators of autophagy and ubiquitin proteosome system (Napoli et al.). On the other side, mitochondrial stress, reflected by mitophagy and mitochondrial fission hyperactivation, also contributes to atrogenes transcription and muscle wasting. The age-related muscle atrophy is also due to an impairment in neuromuscular junction efficiency and reduced myogenesis capacity. Based on the LITOE sub-study, diet-induced weight loss plus resistance and aerobic exercise training reduces myocellular stress affecting all those pathways (except for neuromuscular junction efficiency assessed measuring circulating C-terminal Agrin fragment) and results in improvement in muscle protein synthesis in response to feeding, muscle strength, physical function and attenuated muscle wasting. Red lines indicate inhibition, green arrows activation, black arrows major pathways activation, while yellow dotted arrows refer to pathways on which diet plus resistance and aerobic exercise have a positive effect.