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Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05 Page 5 of 35

[25]
adipocyte hypertrophy and obesity during aging . Accumulation of senescent cells, inflammation-inducing
mechanical stress (e.g., expansion of extracellular matrix), systemic inflammation, and exogenous
[26]
lipopolysaccharides (LPS) may all contribute to adipose tissue dysfunction during aging . Of course, aging-
associated susceptibility to obesity can also trigger adipose tissue inflammaging. Considering adipose tissue
dysfunction is a determinant of obesity and prevalent in aged individuals, it may be a novel therapeutic
target for anti-obesity and anti-aging strategies.

Low-grade systemic inflammation as a marker of obesity and aging
[23]
Like aging, obesity is associated with a state of chronic low-grade inflammation . As a result of weight gain
or obesity, WAT undergoes a phenotypic change from lean to inflamed and dysfunctional. Under a lean
status, WAT is enriched with anti-inflammatory immune cells and regulates whole-body metabolism
through the secretion of adipose tissue-specific cytokines, known as adipokines (e.g., leptin, adiponectin,
[27]
omentin, tumor necrosis factor-alpha (TNF)-α, interleukin (IL)-6, resistin, etc.) . However, under an obese
phenotype, multiple types of pro-inflammatory immune cells infiltrate WAT to trigger an inflammatory
cascade and dysregulate adipokine expression. Inflamed adipocytes then secrete pro-inflammatory
[28]
cytokines locally and systemically, impacting distal organs . Sustained overnutrition maintains WAT
expansion and chronic, low-grade inflammation, making obesity an inflammatory immune disease.
Evidence of systemic and tissue-specific inflammation in obesity is well-established; in fact, serum
inflammatory markers act as obesity biomarkers in clinical trials . The role of inflammation in obesity is
[29]
[18]
also proposed to mediate its link to other diseases, such as metabolic syndrome (MetS) and cancer . As
stated earlier, low-grade inflammation is a hallmark of aging. The concept of inflammation increasing with
[12]
age, termed “inflammaging”, was introduced more than two decades ago . It results from chronic
physiological stimulation of the innate immune system, leading to increased circulating levels of pro-
inflammatory cytokines and biomarkers [e.g., C-reactive protein (CRP)] and a state of chronic, low-grade
inflammation. Today, inflammation is understood to be a cornerstone of many age-related diseases,
including metabolic diseases . In particular, metaflammation occurs from excessive nutrient intake or
[12]
[30]
overnutrition and sustains various metabolic disorders, such as obesity and type 2 diabetes .
Overproduction of ROS is also associated with obesity, along with a decrease in antioxidants, which
together lead to oxidative stress and further the complications of obesity . A similar impact is observed
[22]
with unhealthy aging, as the accumulation of ROS is responsible for many age-related functional losses.
Inflammation is therefore a widespread and opportunistic target for the treatment and/or management of
obesity and aging.

Evidence of disabled autophagy in obese and aged individuals
Autophagy (i.e., macroautophagy) is a conserved biological process by which cells perform self-eating to
enable the degradation of unnecessary or damaged intracellular components . Autophagic activity
[31]
maintains the orderly recycling of cellular components, protects cells against stress, and generates energy
through ATP production, thereby essential for health homeostasis. The core process of autophagy is
initiated by the inhibition of the mechanistic target of rapamycin (mTOR) or activation of 5’ AMP-activated
protein kinase (AMPK), typically in response to stress (e.g., state of starvation) or physical activity . mTOR
[32]
and AMPK are considered master regulators of cellular metabolism, growth, and survival (e.g., autophagy
[13]
pathways). However, autophagic activity declines with age and is now considered a hallmark of aging . A
reduction in autophagy-required genes and proteins (e.g., ATGs, Sirt1) in aged individuals may influence
age-associated autophagy decline, although exact mechanisms remain unknown . Inhibition of autophagy
[32]
accelerates the aging process and several disease pathologies, including neurodegenerative disorders.
Specifically, age-related protein aggregation may occur because of decreased autophagic activity, leading to
neurodegenerative disorders, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS).
Dysfunctional autophagy is also implicated in many metabolic diseases, including obesity, insulin resistance,