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Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05 Page 15 of 35

Biological agents for the treatment of obesity and aging
Biological therapies, represented by monoclonal antibodies (e.g., anti-TNF-α agents), have been developed
to neutralize pro-inflammatory cytokines for a variety of immune-mediated inflammatory diseases (e.g.,
rheumatoid arthritis, plaque psoriasis, ulcerative colitis, etc.) . Considering the immune-related
[137]
dysfunction associated with obesity and aging, the use of biological agents for their treatments is a
promising idea. In aging mice, treatment with a TNF-α inhibitor (i.e., etanercept) led to significantly
improved muscle function and lifespan, suggestive of therapeutic potential against sarcopenia . In the
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context of aging, Chimeric antigen receptor (CAR) T-cells can be used to target upregulated, age-associated
proteins (e.g., uPAR or β-galactosidase) on senescent cells to safely and effectively eliminate senescent
[139]
cells . This groundbreaking study also found uPAR CAR T cells to be therapeutically active against diet-
induced obesity by promoting weight loss and improving glucose homeostasis. However, direct
investigation into biological agents for the treatment of obesity is lacking. Many studies have considered the
impact of such therapies on obesity as a comorbidity of psoriasis, a disease commonly treated with
biologics. For example, a recent study compared the use of biological agents and conventional treatments
for obese and non-obese psoriasis patients . Findings showed successful treatment of psoriasis by IL-17
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and IL-23 inhibitors in obese patients, which are aligned with previous reports . On the contrary, TNF-α
[141]
blockers are not recommended for obese patients, as they are reportedly associated with an increase in body
weight and BMI . As obesity and psoriasis share remarkably similar underlying mechanisms, anti-
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[143]
psoriatic therapies may also be effective in treating obesity . However, research is significantly lacking in
this area. Pre-clinical and clinical studies are needed to validate the use of new-generation biological agents
for obesity and aging. Given their favorable safety profiles and minimal adverse effects, biological agents
may act as alternative therapies to pharmacotherapies based on significant findings.

Pharmacological treatment and management of obesity and aging
For individuals who have an inadequate response to lifestyle interventions, experts recommend using
pharmacotherapy as an adjunct to lifestyle intervention . Current U.S. Food and Drug Administration
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(FDA)-approved anti-obesity medications target peripheral and central pathways to reduce appetite and
increase satiety [145,146] ; however, they are limited by reported side effects [Table 2]. For severely obese
(BMI ≥ 40) individuals, bariatric surgery and implanted devices are available, though they are more invasive
and expensive than medications. Although new drugs are undergoing FDA consideration (e.g., Tirzepatide),
the mechanisms of action are similar to the currently approved drugs, leading to similar safety profiles.
Other medications are approved for rare obesity subtypes, as opposed to general obesity, such as
Metreleptin for congenital or acquired generalized lipodystrophy and Setmelanotide for individuals with
genetic variants of obesity (e.g., proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, leptin
receptor). In addition, some drugs share a mechanism of action with weight-loss therapies but are approved
for other indications. For example, semaglutide is an injectable drug that mimics the action of GLP-1.
Semaglutide is approved for weight loss as Wegovy® , as well as for the treatment of type 2 diabetes as
[145]
[147]
Ozempic®, with the two drugs differing in dosage, administration, and indication . However, the off-label
use of Ozempic® for weight loss has gained public notoriety . Despite the numerous available options,
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there is a great demand for novel anti-obesity therapies with revised therapeutic targets, superior efficacy
and minimal side effects compared to currently approved agents.

Anti-aging therapeutics, or geroprotective agents, extend lifespan, delay or improve aging hallmarks to a
youth-like state, improve the overall quality of life, delay the progression of age-related diseases and/or
increase resistance to adverse factors . These agents should also exhibit low toxicity and have a
[149]
conservative target and mechanism of action. Common aging targets include AMPK, the sirtuin family of
proteins [e.g., Sirtuin 1 (Sirt1)], nicotinamide phosphor-ribosylltransferase (NAMPT), phosphatidylinositol-
3-kinase (P13K)/Akt, mTOR, cyclic adenosine phosphate-dependent protein kinase (PKA), Forkhead Box