Healthy Aging Research
Open Access

Modulating Inflammation to Extend Lifespan in Aging Populations

Naoya Waldmann^{* *}Correspondence: Naoya Waldmann, Department of Global Health Research, University of Pennsylvania, Philadelphia, USA, Email:

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Description

Aging is a complex, multifactorial process characterized by a gradual decline in physiological functions and an increased susceptibility to chronic diseases. Among the myriad hallmarks of aging, chronic low-grade inflammation—often referred to as “inflammaging”—has emerged as a key contributor to age-related functional decline and disease vulnerability. The term “inflammaging” describes a persistent, systemic proinflammatory state that arises in the absence of overt infection, often fueled by immunosenescence, oxidative stress, cellular senescence, and microbial translocation. This chronic inflammatory state not only accelerates biological aging but also contributes to the pathogenesis of diseases such as atherosclerosis, Alzheimer’s disease, type 2 diabetes, cancer, and sarcopenia.

The inflammatory response is a protective mechanism designed to eliminate harmful stimuli and initiate tissue repair. However, when inflammation becomes dysregulated or chronic, it leads to tissue damage, fibrosis, and the propagation of further inflammatory signals. In aging populations, modulating this chronic inflammation through therapeutic and lifestyle interventions is increasingly viewed as a viable approach to extend lifespan and promote healthspan—the period of life spent in good health.

One of the primary sources of chronic inflammation in aging is cellular senescence. Senescent cells, which accumulate with age, no longer divide but remain metabolically active and secrete a range of pro-inflammatory cytokines, chemokines, and proteases known collectively as the Senescence-Associated Secretory Phenotype (SASP). The SASP contributes to tissue dysfunction and the spread of senescence to neighboring cells, thereby creating a vicious cycle of inflammation and damage. Targeting the SASP through senolytic drugs or SASP inhibitors has shown promise in preclinical studies for reducing inflammation and improving tissue function in aged organisms.

The immune system itself undergoes profound remodeling with age, a process known as immunosenescence. This includes diminished function of adaptive immunity, particularly T and B lymphocytes, alongside an overactive and less regulated innate immune response. Aging monocytes and macrophages often exhibit heightened basal levels of pro-inflammatory cytokines such as Interleukin-6 (IL-6), Tumor Necrosis Factor-Alpha (TNF- α), and C-Reactive Protein (CRP), which are key biomarkers of systemic inflammation and predictors of mortality in elderly cohorts. Therapeutic strategies that recalibrate immune responses—such as caloric restriction, exercise, and pharmacological agents—have been investigated for their capacity to lower inflammatory markers and restore immune balance.

Similarly, physical activity is a potent anti-inflammatory intervention. Regular moderate exercise has been shown to decrease systemic inflammation by lowering visceral fat mass—a significant source of pro-inflammatory adipokines—and by promoting the release of anti-inflammatory cytokines from skeletal muscle, such as Interleukin-10 (IL-10) and Interleukin-1 Receptor antagonist (IL-1Ra). Exercise also improves mitochondrial function, insulin sensitivity, and endothelial health, all of which are important for mitigating chronic inflammation and extending healthspan.

Pharmacological interventions have also been explored in the context of inflammaging. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like aspirin have been evaluated for their effects on age-related diseases and longevity. However, long-term NSAID use carries the risk of gastrointestinal and cardiovascular side effects, making them less suitable for chronic use in elderly populations. Alternatively, newer anti-inflammatory agents such as Interleukin-1β (IL-1β) blockers (e.g., canakinumab) have shown efficacy in reducing cardiovascular events and may hold promise in aging interventions, although their cost and immunosuppressive effects require careful consideration.

Metformin, a widely prescribed drug for type 2 diabetes, has garnered significant interest for its anti-aging properties. It reduces inflammation through multiple mechanisms, including inhibition of mitochondrial complex I, activation of AMP-activated Protein Kinase (AMPK), and suppression of NF-κB signaling. Observational studies have suggested that metformin use is associated with reduced cancer incidence and improved cognitive function in older adults. Ongoing clinical trials such as the Targeting Aging with Metformin (TAME) study aim to assess whether metformin can delay the onset of age-related diseases and mortality by modulating inflammation and other aging-related pathways.

In recent years, the role of dietary bioactive compounds in modulating inflammation has gained traction. Polyphenols such as resveratrol, curcumin, and Epigallocatechin Gallate (EGCG) exhibit anti-inflammatory effects by scavenging free radicals, inhibiting NF-κB activation, and modulating the expression of inflammatory genes. These compounds, found in foods like berries, turmeric, and green tea, may contribute to the longevity benefits observed in populations adhering to plant-rich diets, such as the Mediterranean or Okinawan diets.

Conclusion

Chronic inflammation is a central feature of biological aging and a driving force behind many age-related diseases. Modulating this inflammatory milieu through evidence-based interventions offers a promising pathway to not only extend lifespan but, more importantly, to enhance the quality of life in aging populations. Continued research into the molecular underpinnings of inflammaging and the development of targeted therapies will be essential in realizing the goal of healthy aging for all. Ultimately, the modulation of inflammation to promote healthy aging and extend lifespan will likely require a multifaceted approach that integrates lifestyle modifications, pharmacological agents, and emerging biotechnologies. Personalized interventions tailored to an individual’s genetic, immunological, and metabolic profiles may offer the most effective strategy for mitigating inflammaging and its deleterious effects.

References

1. Iyer SR, Shah SB, Lovering RM. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021;22:8058.

   [Crossref] [Google Scholar] [PubMed]

2. Xue Y, Yin R, Yin L, Qin R, Wang X, Li YS, et al. Dietary microRNAs in aging: sources, mechanisms, translational potential, and future directions. Food Funct. 2025.

   [Crossref] [Google Scholar] [PubMed]

3. Deng M, Chen W, Wang X. Characteristics of gut microbiota in longevity populations in China and its relationship with healthy aging. Medicine. 2025;104(31):e43633.

   [Crossref] [Google Scholar] [PubMed]

4. O’Connor MK, Szemko J, McLaren JE, Moo LR, Metcalf EE, Nguyen A, et al. A 20-week, randomized controlled trial to determine the efficacy of the Aging Well through Interaction and Scientific Education-Action Plan (AgeWISE-AP) program in older Veterans. BMC Geriatr. 2025;25(1):588.

   [Crossref] [Google Scholar] [PubMed]

5. Lawton MP. The Philadelphia geriatric center morale scale: A revision. J Gerontol. 1975;30(1):85-89.

   [Crossref] [Google Scholar] [PubMed]

6. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613.

   [Crossref] [Google Scholar] [PubMed]

7. Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. CHAMPS physical activity questionnaire for older adults: outcomes for interventions. Med Sci Sports Exerc. 2001;33(7):1126-1141.

   [Crossref] [Google Scholar] [PubMed]

8. Allarini T, Van Lent DM, Brunner J, Schröder A, Wolfsgruber S, Altenstein S, et al. Mediterranean diet, alzheimer disease biomarkers, and brain atrophy in old age. Neurology. 2021;96(24):e2920-e2932.

   [Crossref] [Google Scholar] [PubMed]

9. Yates LA, Ziser S, Spector A, Orrell M. Cognitive leisure activities and future risk of cognitive impairment and dementia: Systematic review and meta-analysis. Int Psychogeriatr. 2016;28(11):1791-1806.

   [Crossref] [Google Scholar] [PubMed]

10. Akbaraly T, Portet F, Fustinoni S, Dartigues J-F, Artero S, Rouaud O, et al. Leisure activities and the risk of dementia in the elderly: Results from the Three-City study. Neurology. 2009;73(11):854-861.

    [Crossref] [Google Scholar] [PubMed]