Chronic inflammation and age-related diseases

The Biological Framework of Inflammaging

The conceptualization of aging has transitioned from a model of inevitable, stochastic mechanical degradation to a biological paradigm centered on interconnected, modifiable cellular hallmarks. Within the discipline of geroscience, chronic, low-grade, sterile systemic inflammation - termed "inflammaging" - has emerged as a unifying nexus connecting the foundational biology of aging to the clinical manifestation of age-related chronic diseases ¹²³. Introduced conceptually in 2000 by Claudio Franceschi and subsequently expanded to incorporate systemic factors by researchers such as Judith Campisi, the inflammaging framework proposes that lifelong exposure to internal and external biological stressors provokes a continuous, maladaptive innate immune response ³⁴⁵⁶⁷.

Unlike acute inflammation, which is a transient, high-amplitude, and localized evolutionary response to acute injury or exogenous pathogens that resolves upon tissue repair, inflammaging is systemic, persistent, and predominantly subclinical ³⁵. It operates in the absence of overt infectious agents, driven instead by damage-associated molecular patterns (DAMPs) and endogenous cellular stress ³⁸. This chronic inflammatory tone is characterized by a baseline elevation in circulating pro-inflammatory cytokines, acute-phase reactants, and chemokines. The most prominent biomarkers of this state include interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and C-reactive protein (CRP) ¹³⁹.

Differentiation from Immunosenescence and Autoimmunity

While the terms are frequently conflated, inflammaging is distinct from, yet inextricably linked to, immunosenescence. Immunosenescence describes the functional decline of the immune system over time. This decline is characterized by thymic involution, a reduced output of naïve T and B lymphocytes, a relative expansion of memory T cells, and diminished vaccine responsiveness ²³¹⁰¹¹. Inflammaging, conversely, reflects a state of hyperactivation and dysregulation within the innate immune compartment ²³¹¹. These two phenomena operate in a feedback loop; chronic inflammation accelerates immune exhaustion, while senescent immune cells actively secrete pro-inflammatory factors ³.

Furthermore, inflammaging must be differentiated from autoimmune and autoinflammatory diseases. Autoimmune conditions involve a breakdown in adaptive immune self-tolerance, leading to the production of disease-specific autoantibodies ¹²¹³¹⁴. Autoinflammatory conditions involve monogenic or polygenic hyperactivation of innate immune pathways that result in acute, recurrent febrile episodes ¹²¹³. Inflammaging is a pervasive, non-specific physiological shift that acts as a risk multiplier for virtually all major age-associated pathologies, including cardiovascular disease, neurodegeneration, metabolic syndrome, and malignancy ³¹²¹³.

The Evolutionary Mismatch and Epidemiological Debate

While inflammaging is widely recognized as a hallmark of aging in modern industrialized medicine, cross-cultural epidemiological research has challenged the assumption that a chronological rise in systemic inflammation is a universal human biological inevitability. A significant debate within geroscience centers on whether inflammaging is a primary, intrinsic driver of aging or an epiphenomenon resulting from modern environmental and lifestyle factors - an evolutionary mismatch ⁹¹⁴¹⁵.

Industrialized Versus Indigenous Inflammatory Profiles

A pivotal 2025 study published in Nature Aging compared the inflammatory profiles of older adults in industrialized populations against those of non-industrialized, Indigenous populations. The research analyzed data from the Italian InCHIANTI cohort and the Singapore Longitudinal Aging Study (SLAS), alongside the Tsimane of the Bolivian Amazon and the Orang Asli of Peninsular Malaysia ¹⁴¹⁶. By assessing a panel of 19 cytokines, researchers identified a distinct, progressive inflammaging signature in the industrialized cohorts, where markers like CRP and TNF-α rose consistently with chronological age and correlated strongly with chronic conditions such as chronic kidney disease ¹⁴¹⁷¹⁸.

This age-related upward trajectory of inflammation was absent in the Indigenous groups ¹⁴¹⁷. The Tsimane and Orang Asli populations exhibited high constitutive baseline levels of inflammation, driven largely by a high burden of endemic infectious diseases and intestinal parasites (affecting approximately 66% of the Tsimane and over 70% of the Orang Asli) ¹⁴¹⁸¹⁹. Despite having elevated inflammatory markers throughout their lifespans, these populations did not exhibit the progressive inflammatory escalation seen in the West, nor did they develop the chronic age-related diseases that plague industrialized societies ¹⁴¹⁹. Conditions such as type 2 diabetes, atherosclerosis, and Alzheimer's disease were exceptionally rare ¹⁴¹⁹.

The Exposome and Context-Dependent Inflammation

These findings suggest that the phenomenon of inflammaging - specifically as defined by a sterile, progressive inflammatory slope leading to tissue degeneration - may be a byproduct of industrialized living conditions ¹⁴¹⁵¹⁷. In environments lacking the acute pathogen load humans evolved to manage, the immune system may misdirect its activity against metabolic byproducts and endogenous cellular damage, resulting in pathological metaflammation ⁹¹⁵. Consequently, systemic inflammation itself may not be universally detrimental per se; rather, its pathological consequences depend heavily on the exposome - the totality of environmental, dietary, and infectious exposures throughout a lifespan ¹⁴¹⁵¹⁸. When immune activity is contextualized by acute infection rather than chronic metabolic stress, it does not necessarily precipitate degenerative morbidity ¹⁴¹⁷²⁰.

Molecular and Cellular Drivers of Inflammaging

Inflammaging is not propagated by a single cellular source, but rather by a network of converging molecular and physiological dysfunctions. Research has identified several core mechanisms that generate the endogenous danger signals and aberrant signaling necessary to sustain this chronic inflammatory state.

Cellular Senescence and the Secretory Phenotype

Cellular senescence is a state of irreversible cell cycle arrest triggered by diverse cellular stressors, including telomere attrition, oxidative stress, and oncogene activation ²³. While senescence initially evolved as a protective mechanism against tumorigenesis and a localized aid to tissue repair, the age-related accumulation of senescent cells becomes highly deleterious ³²¹. This toxicity is mediated almost entirely by the senescence-associated secretory phenotype (SASP) ²³²².

The SASP is a complex, highly heterogeneous secretome comprising pro-inflammatory cytokines (such as IL-6, IL-1α, and IL-1β), chemokines (such as CXCL8/IL-8 and CCL2), growth factors, and matrix metalloproteinases ³¹³²³. Through autocrine and paracrine signaling, SASP factors reinforce the senescence arrest within the originating cell while simultaneously inducing secondary senescence in neighboring healthy cells, propagating inflammation throughout the tissue microenvironment ¹³²⁴. Key transcriptional regulators of the SASP include NF-κB, GATA4, and C/EBPβ, which are activated by persistent DNA damage responses and regulated heavily by the p38 mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways ³²⁵. Data from the Baltimore Longitudinal Study of Aging indicates that proteins secreted by senescent monocytes can accurately predict various clinical traits, including frailty indices, walk speed, blood pressure, and hemoglobin A1c levels ²⁹.

Cytosolic DNA Sensing and cGAS-STING Activation

A critical molecular bridge between intracellular damage and extracellular inflammaging is the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling pathway ⁸²²³⁰. The cGAS-STING axis acts as an innate immune sensor designed to detect mislocalized double-stranded DNA (dsDNA) in the cytosol, which is traditionally a marker of viral or bacterial infection ⁸²⁶. During biological aging, genomic instability and mitochondrial dysfunction lead to the leakage of self-nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) into the cellular cytoplasm ⁸³⁰²⁶.

Upon binding this mislocalized cytosolic DNA, cGAS synthesizes the second messenger cGAMP, which activates the STING protein ⁸. STING activation triggers the phosphorylation of transcription factors, including IRF3 and NF-κB, leading to the robust transcription of type I interferons (IFN-I) and SASP-related pro-inflammatory cytokines ⁸²⁶. Recent investigations utilizing human fibroblasts passaged in culture and models of Hutchinson-Gilford Progeria Syndrome have revealed non-canonical STING activity during aging. In these senescent states, STING can localize to the endoplasmic reticulum, nuclear envelope, and chromatin, driving sterile inflammation and the SASP without a massive parallel increase in cGAMP production ³⁰. The chronic activation of the cGAS-STING pathway is heavily implicated in systemic decline, microglial chemotaxis in neurodegeneration, and localized tissue deterioration such as UV-induced photoaging of the skin ²⁶³².

Clonal Hematopoiesis of Indeterminate Potential

Clonal hematopoiesis of indeterminate potential (CHIP) represents a profound link between acquired genetic instability and systemic inflammaging ³³²⁷²⁸. CHIP is defined as the age-related clonal expansion of circulating leukocytes descended from a single somatically mutated hematopoietic stem cell (HSC), occurring in the absence of overt hematological malignancy or cytopenia ³³²⁷²⁸. The prevalence of CHIP increases markedly with age, becoming detectable in 10% to 20% of individuals over the age of 70 ²⁷²⁹³⁰. The most frequently mutated driver genes encode epigenetic regulators, predominantly DNMT3A, TET2, and ASXL1, which account for approximately 80% of all CHIP cases ^27283038.

While CHIP confers a moderately increased risk for myeloid malignancies, its most significant clinical impact is its systemic inflammatory footprint, which severely elevates the risk of atherosclerotic cardiovascular disease (ASCVD), heart failure, and overall mortality ^27293831. Mutant HSCs give rise to circulating myeloid cells (such as macrophages and monocytes) that exhibit an intrinsically hyper-inflammatory phenotype ⁷¹². For instance, TET2-deficient macrophages exhibit exaggerated activation of the NLRP3 inflammasome, leading to the overproduction of IL-1β and IL-6 ⁷²⁹³².

The relationship between CHIP and inflammaging appears bidirectional. While CHIP clones generate systemic inflammation, the inflammatory environment itself confers a selective fitness advantage to these mutant clones over normal HSCs, accelerating their expansion in a phenomenon termed "clonal inflammaging" ⁷³³²⁸. Clinical risk is highly contingent upon the specific mutation and variant allele frequency (VAF). Analyses of biobank data indicate that cardiovascular risk associated with TET2 mutations is overwhelmingly driven by putative loss-of-function variants rather than missense variants ³¹. Furthermore, non-DNMT3A variants (such as TET2 and ASXL1) show stronger correlations with incident heart failure and elevated IL-6 levels than the more ubiquitous DNMT3A mutations ³⁰³⁸.

Gut Dysbiosis and Metabolic Endotoxemia

The gut microbiome undergoes substantial compositional and functional shifts with advancing age, contributing extensively to inflammaging via the gut-barrier axis ^25333435. Aging is frequently accompanied by a reduction in overall microbial diversity, a decline in beneficial bacteria (e.g., Bifidobacterium, Lactobacilli, and short-chain fatty acid-producing Faecalibacterium), and a simultaneous overrepresentation of pro-inflammatory taxa, particularly from the Proteobacteria and Enterobacteriaceae families ²⁵³³³⁴.

This dysbiosis compromises the integrity of the intestinal epithelial barrier, resulting in increased intestinal permeability, colloquially known as "leaky gut" ²⁵³⁴. The degradation of the barrier allows for the translocation of microbial products - most notably lipopolysaccharides (LPS), a highly immunogenic component of Gram-negative bacterial cell walls - into the systemic circulation ²⁵³³³⁵. The chronic presence of circulating LPS triggers "metabolic endotoxemia," continuously activating Toll-like receptors (TLRs) and Nod-like receptors (NLRs) on innate immune cells ²⁵³³. This chronic TLR activation sustains NF-κB signaling, perpetuating the production of systemic inflammatory mediators ³³³⁴. Dysbiosis also alters the metabolism of bile acids, modifying signaling through the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), which further influences systemic energy balance and lipid metabolism ³⁶³⁷.

Pathological Integration Across Organ Systems

Inflammaging acts as a central pathophysiological node, utilizing systemic inflammatory mediators to disrupt tissue homeostasis and drive discrete morbidities across multiple organ systems.

Cardiovascular and Cerebrovascular Deterioration

The vascular endothelium is highly susceptible to the chronic inflammatory milieu. Inflammaging promotes endothelial dysfunction, arterial stiffness, and accelerated atherogenesis by upregulating adhesion molecules that facilitate the recruitment and subendothelial infiltration of monocytes ^10132932.

This process is radically accelerated in individuals harboring CHIP mutations. Patients carrying DNMT3A or TET2 mutations exhibit highly vulnerable coronary plaque characteristics compared to non-carriers, including larger lipid cores, thinner fibrous caps, smaller minimal lumen areas, and intense macrophage infiltration ³². In ST-segment elevation myocardial infarction (STEMI) cohorts, TET2 mutation carriers demonstrate an independently worse prognosis, facing a hazard ratio of 3.57 for major adverse cardiovascular events (MACE) and a hazard ratio of 3.06 for death compared to patients without the mutation ³². The inflammaging cascade also extends to the cerebral microvasculature, where it promotes cerebral small vessel disease (CSVD), blood-brain barrier disruption, cerebral microhemorrhages, and vascular contributions to cognitive impairment and dementia (VCID) ³⁸.

Neuroinflammation and Cognitive Decline

In the central nervous system, inflammaging manifests as a progressive shift in the glial compartment. Microglia, the resident immune cells of the brain, gradually lose their homeostatic regulatory functions and adopt a primed, pro-inflammatory phenotype ³²³⁹. Persistent activation of the NLRP3 inflammasome and cGAS-STING pathways within microglia drives the continuous secretion of IL-1β, IL-18, and TNF-α ³²³⁹. This hostile local environment erodes synaptic plasticity, compromises trophic support (such as Brain-Derived Neurotrophic Factor, BDNF), and restricts adult neurogenesis ³⁹.

Gut dysbiosis acts as a remote driver of neuroinflammation along the microbiota-gut-brain axis ³⁶⁴⁰. Reductions in neuroprotective short-chain fatty acids (SCFAs) and alterations in tryptophan-derived indoles and trimethylamine-N-oxide (TMAO) influence microglial activation and blood-brain barrier integrity ³⁶⁴⁰. Transcriptomic analyses of Alzheimer's disease (AD) models reveal that microbial metabolites influence Axon guidance, ErbB, and MAPK signaling pathways, while altering the expression of regulatory microRNAs (such as hsa-let-7c and hsa-mir-125b-2) linked to protein aggregation and synaptic dysfunction ³⁷⁴¹.

Oncogenesis and Tumor Microenvironment Remodeling

The relationship between inflammaging, cellular senescence, and cancer is highly complex and paradoxical. In the early stages of oncogenesis, the induction of senescence acts as a potent tumor-suppressive barrier ²¹²³⁴². Premalignant cells undergoing oncogene-induced senescence (e.g., via KRAS or Myc alterations) enter cell cycle arrest, and the ensuing SASP recruits innate immune cells, such as NK cells and macrophages, to clear the damaged tissue ^21232442.

However, in the context of persistent inflammaging and established tumor architecture, the SASP becomes profoundly pro-tumorigenic ²¹²³. Chronic SASP activity physically remodels the extracellular matrix and establishes a permissive, immunosuppressive tumor microenvironment (TME) ²³⁴². SASP components polarize macrophages toward a tumor-promoting M2 phenotype, recruit regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and induce exhaustion in cytotoxic T cells ²¹²³. Specific SASP factors like IL-6 and IL-8 have been shown to directly induce epithelial-to-mesenchymal transition (EMT) and promote cancer cell stemness, driving metastasis, therapeutic resistance, and immune evasion ²¹²⁴. This creates a "cancer reparative trap," where continuous tissue damage and subsequent reparative immune suppression provide the exact conditions necessary for malignant survival ⁴³.

Metaflammation and Sarcopenic Obesity

Inflammaging intersects closely with metaflammation - the chronic low-grade inflammation triggered by nutrient overload and metabolic excess ⁹. Excess visceral adipose tissue, particularly in older adults, ceases to be an inert storage depot and functions as an active endocrine organ ⁹. It secretes pro-inflammatory adipokines (e.g., leptin) while simultaneously downregulating protective factors (e.g., adiponectin) ⁹. This pathophysiological shift transforms fat tissue from a bystander into a primary driver of systemic insulin resistance and cardiovascular risk ⁹. The combination of visceral fat accumulation and inflammaging severely impacts muscle homeostasis, contributing to sarcopenic obesity. This phenotype is characterized by simultaneous muscle atrophy and fat gain, resulting in reduced physical function, heightened frailty, and an increased susceptibility to heart failure with preserved ejection fraction (HFpEF) ⁹³⁵.

The Centenarian Paradox and Blue Zone Immunology

If systemic inflammation is inherently destructive, the physiological profiles of exceptionally long-lived individuals - centenarians - present a profound biological paradox. Extensive demographic and biological research into populations in validated "Blue Zones" (regions with extraordinary longevity, including Sardinia, Italy; Okinawa, Japan; Nicoya, Costa Rica; Ikaria, Greece; and Loma Linda, California) has revealed unique immune configurations ^52445455. The demographic validity of these regions has been rigorously confirmed through multiple independent documentary sources, ruling out age-exaggeration fraud ⁵⁵⁴⁵⁴⁶.

The Pro-Inflammatory Baseline

Contrary to the logical assumption that exceptional longevity requires an absence of inflammation, centenarians exhibit significantly elevated levels of circulating pro-inflammatory cytokines. Plasma analyses consistently show higher levels of CRP, IL-6, TNF-α, IFN-γ, IL-12, and IL-23 in centenarians compared to younger controls, effectively displaying robust markers of advanced inflammaging ⁴⁷⁴⁸⁴⁹. However, unlike typical older adults who suffer from inflammaging-induced morbidities, centenarians demonstrate exceptional physiological resilience, remaining largely free of cancer, severe cardiovascular disease, and dementia ⁴⁴⁴⁷.

Immune Signatures of Exceptional Longevity

High-resolution, multi-omics single-cell profiling of centenarians, their offspring, and community controls has elucidated the mechanics of this resilience ⁶¹⁵⁰. Centenarians maintain a radically reshaped, highly functional immune landscape that streamlines rather than shuts down ⁶¹⁵⁰. They exhibit leaner CD4+ T cell and B cell pools, but maintain or enhance cytotoxic natural killer (NK) cell and CD8+ T cell networks ⁶¹⁵⁰⁵¹. Flow cytometry assays reveal higher granzyme B expression in NK cells and increased HLA-E+ NK cells, indicating an immune system highly optimized for the efficient clearance of pathogens, senescent cells, and emerging malignancies ⁶¹⁵⁰.

Crucially, centenarians actively balance their high pro-inflammatory tone with a precise anti-inflammatory counter-response. Alongside standard anti-inflammatory molecules like IL-10, they exhibit unique increases in Th2-shifting cytokines like IL-19 ⁴⁷⁴⁸⁵². Furthermore, the ratio of pro-inflammatory Th17 cells to immunosuppressive regulatory T cells (Tregs) is uniquely optimized. Whereas the general aging population experiences a deleterious elevation in the Th17/Treg ratio, centenarians exhibit a decrease, with their Th17 cells adopting a less inflammatory secretory phenotype ⁴⁷⁵¹. The extreme longevity observed in Blue Zones suggests that the danger of inflammaging lies not strictly in the baseline presence of cytokines, but in the failure of the immune system to achieve resolution and maintain cytotoxic functional efficiency ²⁹⁵⁰.

Clinical Interventions and Therapeutics

Recognizing inflammaging as a modifiable root cause of chronic disease has spurred the development of diverse pharmacological and nutritional interventions. These therapies aim to modulate immune tone, clear senescent cell burden, and address specific genetic drivers of systemic inflammation.

Senolytics and Senomorphics

Senolytics are a class of therapeutics designed to selectively induce apoptosis in senescent cells by inhibiting the pro-survival pathways (e.g., BCL-2/BCL-xL networks, p21, HIF-1α) that these cells rely upon to evade death ⁵³⁵⁴. The most clinically studied regimen is the combination of Dasatinib (a tyrosine kinase inhibitor) and Quercetin (a flavonoid), referred to as D+Q. While an early open-label pilot trial demonstrated that D+Q reduced senescent cell burden in the adipose tissue of patients with diabetic kidney disease within 11 days, broader systemic efficacy has proven challenging ⁵⁴⁵⁵. A 2024 Phase 2 randomized, placebo-controlled trial examining intermittent D+Q therapy in postmenopausal women found no significant long-term impact on primary markers of bone degradation over 20 weeks, highlighting the limitations of current systemic, first-generation senolytics ⁵⁶⁵⁷.

Targeted local delivery has shown greater clinical utility. Unity Biotechnology's UBX1325, a highly selective BCL-xL inhibitor, demonstrated significant efficacy in the Phase 2b ASPIRE trial for diabetic macular edema, achieving visual acuity gains comparable to standard anti-VEGF therapies without severe systemic toxicity ⁵⁴⁵⁸⁵⁹. As first-generation senolytics face scrutiny regarding off-target toxicity to healthy cells (such as platelets), the field is advancing toward senomorphics - agents that suppress the SASP without killing the cell - and engineered immune therapies, including CAR-T cells targeting specific senescence surface antigens ⁵³⁵⁸.

Metformin, a well-established antidiabetic drug, is currently being evaluated as a senomorphic and broad-spectrum anti-inflammaging agent ⁶⁰. A 2024 community-based randomized trial demonstrated that oral metformin administration (2000 mg/day) significantly reduced knee pain over six months in patients with osteoarthritis and obesity, potentially due to its systemic anti-inflammatory properties ⁶¹. The landmark Targeting Aging with Metformin (TAME) trial is actively assessing the drug's capacity to delay the onset of multiple age-related morbidities across 3,000 individuals, attempting to secure the first FDA indication for treating biological aging ⁶⁰.

Janus Kinase Inhibitors and Cytokine Modulation

Janus kinase (JAK) inhibitors, utilized broadly for autoimmune conditions like rheumatoid arthritis and inflammatory bowel disease (IBD), directly interrupt the intracellular signaling cascades of numerous inflammaging-associated cytokines ⁶²⁶³⁶⁴. Recent evaluations suggest they may be repositioned to address the cardiovascular risks associated with systemic sterile inflammation. A 2025 pilot study demonstrated that JAK inhibitor therapy significantly reduced systemic inflammation and carotid intima-media thickness (cIMT) in arthritis patients over 12 months, indicating potential benefits in attenuating early subclinical atherosclerosis ⁶²⁶⁵.

While safety concerns regarding malignancy and major adverse cardiovascular events (MACE) have been raised with certain older JAK inhibitors (e.g., tofacitinib), massive 2025 network meta-analyses and European Alliance of Associations for Rheumatology (EULAR) guidelines indicate that, on aggregate, JAK inhibitors do not cause statistically significant increases in overall malignancy rates compared to biologics ⁶³⁶⁴⁶⁶. Furthermore, specific next-generation agents like deucravacitinib have shown a capacity to significantly decrease the risk of venous thromboembolism (VTE) and cardiovascular events compared to placebo, emphasizing the need for tailored, agent-specific clinical applications ⁶³.

Nutritional Modulation and Lipid Therapies

Nutritional modulation of inflammation offers a highly accessible intervention strategy. Omega-3 polyunsaturated fatty acids (EPA and DHA) combat inflammaging by competing with arachidonic acid for cyclooxygenase and lipoxygenase enzymes, thereby reducing the production of pro-inflammatory prostaglandins and leukotrienes ⁷⁹⁶⁷. Comprehensive 2025 and 2026 meta-analyses confirm that supplementation of 1 to 3 grams of EPA/DHA daily significantly reduces circulating IL-6, TNF-α, IL-1β, and CRP ⁷⁹⁶⁷. Clinical efficacy has been notably demonstrated in specialized cohorts; omega-3 supplementation significantly reduced hospital stays and complication risks in gastrointestinal cancer patients, and diminished hyper-inflammatory responses (lowering SOFA scores) and 28-day mortality in critically ill ICU patients ⁶⁸⁶⁹.

In the specific context of CHIP-induced inflammaging, routine lipid-lowering therapies may provide unexpected disease-modifying benefits. The 2025 English Longitudinal Study of Ageing (ELSA), which analyzed over 13,000 blood samples, revealed that the use of statins is associated with significantly slower clonal growth of TET2 mutations over a decade ⁷⁰. Furthermore, participants with CHIP receiving statins for primary prevention experienced a lower incidence of heart attack or stroke than non-CHIP individuals on the identical therapy. This suggests that statins may specifically suppress the inflammatory feed-forward loop that provides a selective fitness advantage to mutant HSC clones, offering a targeted preventative strategy for clonal inflammaging ⁷⁰.