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Page 4 of 35 Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05

[10]
diseases . Age-related diseases include physical ailments - such as cancer, metabolic disease, cardiovascular
disease, musculoskeletal disorders, or frailty - and cognitive impairment via neurodegenerative diseases
(e.g., Alzheimer’s disease, Parkinson’s disease) [10,11] . Introduced by López-Otín et al. in 2013, the traditional
hallmarks of aging are evident on molecular, cellular, and systemic levels and include genomic instability,
telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial
[12]
dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication . However,
López-Otín et al. recently extended the list of aging hallmarks to include disabled macroautophagy, chronic
[13]
inflammation, and microbial dysbiosis . These influential additions may encourage the development of
novel anti-aging strategies. Overall, individual aging hallmarks are interconnected and contribute to the
progression of aging and age-associated diseases. Further research may use the identified hallmarks as
biomarkers to study the aging process and anti-aging therapeutics.

THE INTERRELATIONSHIP BETWEEN OBESITY AND AGING
Obesity accelerates aging
As the global prevalence of obesity increases, so does the risk of dying prematurely. The association between
obesity and years of life lost (YLL) has become a popular area of study in recent years. Evidence shows an
increase in all-cause mortality in both overweight and obese individuals, with hazard ratios higher at
younger ages than older ages and higher in men than women, across four continents . Similarly, an
[14]
Australian study showed that adults aged 20-39 years with obesity and severe obesity, compared to healthy
weight adults, lose 5.6-7.6 and 8.1-10.3 years, respectively, with men losing 27.7% more life years compared
to women . Earlier research based in the US corroborates this, demonstrating that obesity shortens
[15]
[16]
lifespan by up to 20 years, especially among younger adults . Obesity also accelerates the onset of age-
associated diseases, including type 2 diabetes , cancer , cardiovascular disease , neurodegeneration, and
[19]
[17]
[18]
[20]
cognitive decline . Obesity and aging share several areas of overlap. A less active lifestyle, poor dietary
habits, genetic predisposition, and dysregulated hormonal signaling and metabolism may cause obesity or
aging [13,21] . In addition, the phenotype and physiological characteristics of obesity closely mimic those of
aging. For example, excess reactive oxygen species (ROS) production and resulting redox imbalance,
mitochondrial dysfunction, and cellular senescence are associated with obesity and aging . Key factors that
[22]
underlie obesity and aging - adipose tissue dysfunction, low-grade systemic inflammation, and disabled
autophagy - will be discussed in greater detail.

Dysfunctional adipose tissue is observed in obesity and aging
Obesity and aging share many hallmarks, such as metabolic dysregulation, insulin resistance, impaired
[22]
immunity, and chronic, low-grade inflammation . Like obesity, aging is also associated with adipose tissue
dysfunction, including WAT redistribution and increased visceral adipose tissue due to reduced
[23]
preadipocyte tissue differentiation . Such changes to adipose tissue may contribute to systemic
inflammation with advancing age. Adipose tissue stores energy as lipids, releasing fatty acids in response to
systemic nutritional and metabolic needs, and is present in the forms of white and brown adipose tissue
(BAT) . Both types of adipose tissue are comprised of adipocytes, stem cells, preadipocytes, immune cells,
[24]
fibroblasts, and endothelial cells. WAT stores energy in the form of triglycerides, while BAT expends energy
via thermogenesis. Moreover, adipose tissue is divided into subcutaneous depots under the skin or visceral
depots that surround internal organs. In obese individuals, visceral depots of WAT expand in size in an
unhealthy manner (i.e., hypertrophy) due to increased lipid storage and in number (i.e., hyperplasia) from
the proliferation of precursor cells rather than sending fat into mature adipocytes. These changes lead to
WAT dysfunction and the promotion of obesity-associated metabolic complications, also leading to ectopic
lipid deposition in non-adipose organs . WAT may also undergo senescence and subsequent hypertrophy
[23]
with obesity, which is also seen with aging. Aging is associated with the progression of WAT dysfunction,
largely through repressed mitochondrial activity which may reduce fatty acid oxidation and lead to