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Page 6 of 35 Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05

[22]
diabetes mellitus, and atherosclerosis . In a healthy state, cells can normalize intracellular fat content by
[32]
performing an autophagy-dependent process, known as lipophagy, to metabolize lipid droplets . However,
following excess intake of insulin and nutrients, autophagy is suppressed in skeletal muscle, adipose tissue,
and the liver due to mTOR activation. Insufficient autophagy results in an unhealthy accumulation of lipid
droplets, protein aggregates, and other potential autophagic substrates, leading to systemic lipotoxicity,
impaired cell function, and eventually cell death. Impaired autophagy may also promote the secretion of
pro-inflammatory cytokines (e.g., IL-1β) and oxidative stress. Likewise, oxidative stress can inhibit
autophagy, thereby triggering endoplasmic reticulum (ER) stress and increased apoptosis in skeletal muscle
and other cell types . Recently, peroxisome proliferator-activated receptor-gamma (PPAR-γ), the master
[22]
[33]
regulator of adipogenesis, was discussed as a potential modulator of autophagy in obesity . Briefly, PPAR-γ
activation increases fat storage in adipose tissue via adipogenesis, decreasing lipotoxicity in the liver and
skeletal muscle. PPAR-γ stimulation may also initiate adipocyte differentiation and autophagy in fat cells,
preventing adipocyte hypertrophy. However, further research is needed to determine the therapeutic
potential of targeting PPAR-γ and other factors to activate autophagy for the improvement of obesity and
aging.

Sarcopenic obesity
Obesity is also accompanied by decreased muscle mass and function, as well as fatigue, due to metabolic
and cellular changes to skeletal muscle from nearby increased adipose tissue . Age-related loss of muscle
[34]
mass and strength or physical performance is an aging phenomenon known as sarcopenia. The common
intersection of obesity and sarcopenia led to the introduction of sarcopenic obesity, defined by a relatively
low muscle mass and strength in combination with obesity. Sarcopenic obesity is mainly triggered by
adipose tissue and skeletal muscle inflammation. The shared mechanisms underlying obesity and aging -
such as WAT expansion, low-grade chronic inflammation, and disabled autophagy - play a part in the
pathogenesis of sarcopenic obesity . In addition, age-related reduction in muscle mass leads to weight gain
[35]
in the form of fat rather than lean mass . The deposition of fat in muscle, or intramyocellular lipids, occurs
[36]
with aging and obesity, impairing muscle function through inflammation and lipotoxicity. These factors
contribute to the development and progression of sarcopenic obesity, though the cellular and molecular
mechanisms underlying the etiology of sarcopenic obesity remain unclear. The typical patient with
[37]
sarcopenic obesity is over the age of 60 years and exhibits a sedentary lifestyle with poor nutrition .
However, sarcopenic obesity is also found in individuals as young as 20-29 years old, although its prevalence
[38]
dramatically increases with age . It is estimated that 11% of today’s global population of adults aged 60 and
older have sarcopenic obesity . Expert consensus on sarcopenic obesity was recently published, defining
[39]
the disease as the co-existence of excess adiposity and low muscle mass/function . There is currently no
[40]
approved pharmacological treatment for sarcopenic obesity. Implementation of a universal definition and
diagnostic criteria for sarcopenic obesity is a critical first step toward proper treatment guidelines.
Moreover, sarcopenia and obesity may act synergistically to elevate the risk of cardiometabolic diseases,
energy imbalance, muscular dysfunction, and, of course, mortality. For example, rates of insulin resistance
and MetS in patients with sarcopenic obesity exceeded those in patients with sarcopenia alone or obesity
alone . Urgent attention and exploration of sarcopenic obesity is therefore required.
[41]

THE GUT MICROBIOME CONNECTS OBESITY AND AGING
The gut as an endocrine organ
The functions of the GI tract are largely regulated by gut hormones. Enteroendocrine cells (EEC) are
dispersed throughout the gut epithelium, making up 1% of the GI epithelial cell population, and collectively
form the largest endocrine system in the human body . EECs modulate GI function by secreting over
[42]
twenty gut regulatory peptides in response to nutrients. Ghrelin, a key hormone produced by EECs in the
stomach, stimulates appetite and growth hormone (GH) release. Contrarily, glucagon-like peptide 1