Journal September 19, 2026 5 min read

What is immunosenescence?

Immunosenescence is the age-associated decline in immune function, marked by thymic involution, reduced T-cell output and chronic low-grade inflammation. This page summarises the research literature on the mechanisms and

peptides-pro Editorial

Immunosenescence is the age-associated remodelling and decline of immune function. It is not a single entity but a collection of phenotypes: thymic involution with reduced naive T-cell output, accumulation of senescent immune cell subsets, telomere shortening in immune cells, and a chronic low-grade inflammatory state. The term is used across the immunology and geroscience literature, and the same phenotypes are described in autoimmune disease, where they appear early rather than late in life [1].

The work in this area centres on thymic output and the T-cell compartment, with the thymus as the primary tissue of interest and thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, as one of the most studied immunomodulatory agents in that context [2].

Research Studies

Immunosenescence in systemic lupus erythematosus

A review of innate and adaptive mechanisms reported that several immunological alterations seen in systemic lupus erythematosus resemble those of physiological ageing. The mechanisms reviewed included telomere shortening, chronic low-grade inflammation, thymic dysfunction, and expansion of senescent immune cell subsets. The authors noted that these age-associated immune phenotypes emerge early in that population and contribute to disease activity, organ damage, and long-term outcomes, including cardiovascular complications [1].

Thymosin alpha-1 and thymic involution

Thymic involution — the age-related shrinkage of the thymus — reduces T-cell production and is associated with chronic inflammation and increased susceptibility to age-related disease. Tα1 has been reported to stimulate T-cell differentiation, enhance thymic output, and modulate dendritic cell and macrophage activity. Preclinical and clinical studies cited in that review reported improved vaccine response in elderly subjects and mitigation of immunosenescence [2].

Thymosin alpha-1 and early-stage NSCLC

A registered trial is exploring the effect of Tα1 on postoperative peripheral blood circulating tumour cells and immunosenescence in patients with early-stage non-small cell lung cancer. The study population is patients with stage I NSCLC [4].

Nicotinamide mononucleotide and immunosenescence in metabolic disorders

A placebo-controlled clinical trial investigated the effect of nicotinamide mononucleotide (NMN) supplementation on immunosenescence in middle-aged and elderly individuals with metabolic disorders, with glucose and lipid metabolism among the outcomes assessed. The rationale given is that metabolic disorders can themselves trigger ageing processes, and that cellular senescence occurs across body systems, with senescence of the immune system termed immunosenescence [3].

Nicotinamide mononucleotide and mesenchymal stem cell ageing

In D-galactose-induced ageing mice and cellular senescence models, co-treatment with NMN was studied as a means of enhancing the anti-ageing capacity of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The reported problem is that an ageing microenvironment induces oxidative stress and senescence in transplanted hUC-MSCs, impairing their capacity to delay immunosenescence. This work is animal- and cell-model based [9].

Alpha-ketoglutarate and surgical stress in older patients

Coronary artery bypass grafting (CABG) is performed in approximately 400,000 patients in the United States each year and invokes a large surgical stress response, with systemic epinephrine rising 33-fold and norepinephrine 3-fold. Local tissue injury produces sterile inflammation and release of damage-associated molecular patterns, which activate neutrophils and a cascade of cytokines, complement, and coagulation changes. A registered trial is examining alpha-ketoglutarate in this geroprotection context in older surgical patients [5].

Taxifolin and ergothioneine in healthy volunteers

Immune function varies across the lifecourse, with a well-understood decline with age that results in impaired vaccination responses and increased risk of infection and severe complications. A trial in healthy volunteers is measuring the impact of taxifolin and ergothioneine on immune biomarkers, noting that diet supplies the energy and building blocks for immune mediators such as antibodies and cytokines and may act indirectly via the gut microbiome [6].

Comparison of studied agents and models

Agent	Model or population	Immune focus
Thymosin alpha-1	Elderly subjects; stage I NSCLC patients	T-cell differentiation, thymic output, vaccine response [2][4]
Nicotinamide mononucleotide	Middle-aged and elderly with metabolic disorders; D-galactose-aged mice and cell models	Immunosenescence markers, metabolic parameters, MSC senescence [3][9]
Alpha-ketoglutarate	Older patients undergoing CABG	Surgical stress response, sterile inflammation [5]
Taxifolin / ergothioneine	Healthy volunteers	Immune biomarkers across the lifecourse [6]

Related mechanisms reported in the literature

Additional reports describe immunosenescence in specific contexts. In menopause, progressive estrogen depletion is associated with mitochondrial dysfunction, oxidative stress, chronic inflammation, genomic instability, and immunosenescence [7]. In bone metabolism, immune cells maintain skeletal homeostasis through cytokine secretion and cell interactions, and disruption by inflammation, autoimmunity, or ageing drives pathological bone disease [8]. Irisin, a muscle-secreted myokine induced by exercise, has been described as a molecular bridge between muscle activity and the immune system, with relevance to the transition toward immunosenescence and vulnerability to acute systemic illness [10].

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