What markers track immunosenescence?

Immunosenescence is the formal term for the age-associated remodelling and decline of immune function. It is not a single analyte but a composite phenotype, and the literature tracks it through several overlapping classes of marker: thymic output and T-cell receptor repertoire diversity, telomere length in leukocyte populations, the expansion of senescent immune cell subsets, and chronic low-grade inflammation — often described as inflammaging. In systemic lupus erythematosus (SLE), an autoimmune disease characterised by chronic immune dysregulation across the lifespan, many of these immunological alterations resemble those seen in physiological aging, including telomere shortening, chronic low-grade inflammation, thymic dysfunction and expansion of senescent immune cell subsets [1].

No single identifier — sequence, formula or molecular weight — defines immunosenescence, because it is a state rather than a molecule. The work in this area centres on thymic output and the T-cell compartment, together with the innate inflammatory signalling that accompanies thymic involution [2].

Research Studies

Thymosin alpha-1 and thymic involution in aging

Aging is characterised by immune decline, mainly due to thymic involution — the age-related shrinkage of the thymus gland — which leads to reduced T-cell production, chronic inflammation and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, has been studied for immunomodulatory, anti-inflammatory and antioxidant properties. In preclinical and clinical studies it has been reported to stimulate T-cell differentiation, enhance thymic output, and modulate dendritic cell and macrophage activity, and to improve vaccine response in the elderly [2].

Thymosin alpha-1 and immunosenescence in early-stage NSCLC

A registered trial has been designed to explore the effect of thymosin alpha-1 on postoperative peripheral blood circulating tumour cells and immunosenescence in patients with early-stage non-small cell lung cancer (NSCLC) [4]. This is a disease-specific population, and the readouts are circulating tumour cells and immunosenescence parameters rather than a general aging cohort.

Nicotinamide mononucleotide and immunosenescence in metabolic disorders

Metabolic disorders have themselves been reported to trigger aging, and cellular senescence can occur across body systems, with senescence of the immune system termed immunosenescence. A placebo-controlled trial investigated the effect of nicotinamide mononucleotide (NMN) supplementation on immunosenescence in middle-aged and elderly people with metabolic disorders, with glucose and lipid metabolism also assessed [3].

Nicotinamide mononucleotide and mesenchymal stem cell senescence in mice and cell models

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been investigated as an anti-ageing therapeutic option, but an ageing microenvironment can induce oxidative stress and senescence in transplanted hUC-MSCs, impairing their capacity to delay immunosenescence. Combining MSC-based approaches with NMN co-treatment has been studied in D-galactose-induced ageing mice and in cellular senescence models [9]. This evidence is animal-only and in vitro.

Alpha-ketoglutarate and surgical stress in older patients

Coronary artery bypass grafting (CABG) is among the most common major surgeries in older patients, performed in approximately 400,000 patients in the United States each year. CABG invokes a large surgical stress response, with systemic epinephrine increasing 33-fold and norepinephrine increasing 3-fold; local tissue injury produces sterile inflammation and release of damage-associated molecular patterns (DAMPs), which activate neutrophils and a cascade of cytokines, complement and coagulation changes, while nociceptor activation drives a neurometabolic response involving the sympathetic nervous system and the hypothalamus-pituitary axis. A registered trial, AEGIS, examines alpha-ketoglutarate in this geroprotection context [5].

Taxifolin and ergothioneine and immune biomarkers in healthy volunteers

Measuring the impact of dietary interventions on immune function is difficult because the immune system is highly responsive to environmental influences, including diet, which supplies energy for immune responses, building blocks for mediators such as antibodies and cytokines, and indirect effects via the gut microbiome. Immune function varies across the lifecourse, with a well-understood decline with age resulting in impaired vaccination responses and increased risk of infections and severe complications. The TaxEr study assessed taxifolin and ergothioneine against immune biomarkers in healthy volunteers [6].

Irisin and the aging immune landscape in sepsis

Irisin, a muscle-secreted myokine induced by exercise, has been described as a molecular bridge between muscle activity and the immune system. In aging, irisin may modulate the transition toward immunosenescence and influence host vulnerability to acute systemic inflammation [10].

Bone immunity and age-related skeletal disease

Bone metabolism is regulated by immune cells that maintain skeletal homeostasis through cytokine secretion and cell interactions; disruption of this regulation by inflammation, autoimmunity or aging drives pathological bone diseases including osteoporosis and rheumatoid arthritis, and single-cell technologies have been applied to resolve these populations [8].

NAD+ and immunosenescence in the menopause context

Menopause is a biological condition associated with progressive estrogen depletion and increased susceptibility to several age-associated disorders. Among the mechanisms discussed in that context are mitochondrial dysfunction, oxidative stress, chronic inflammation, genomic instability and immunosenescence [7].

Markers compared across study contexts

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Sources

• [1] Immunosenescence in systemic lupus erythematosus: Mechanisms, clinical consequences, and therapeutic implications — https://pubmed.ncbi.nlm.nih.gov/42498095/
• [2] Aging and Thymosin Alpha-1 — https://europepmc.org/article/PMC/PMC12692621
• [3] The Impact of Nicotinamide Mononucleotide Sustained-release Tablets on Immunosenescence and Metablism in Middle-aged and Elderly Individuals With Metabolic Disorders — https://clinicaltrials.gov/study/NCT06907329
• [4] Immuno-effect of Tα1 for Stage I NSCLC — https://clinicaltrials.gov/study/NCT06598839
• [5] Alpha Ketoglutarate Enhances Geroprotection In Surgery (AEGIS) — https://clinicaltrials.gov/study/NCT07031128
• [6] Taxifolin/Ergothioneine and Immune Biomarkers in Healthy Volunteers (TaxEr) — https://clinicaltrials.gov/study/NCT05190432
• [7] Nicotinamide Adenine Dinucleotide and Its Anti-aging Effects in the Context of Longevity and Menopause — https://pubmed.ncbi.nlm.nih.gov/42669985/
• [8] Advances in the study of the role of bone immunity in physiological and pathological processes related to bone metabolism — https://pubmed.ncbi.nlm.nih.gov/42546515/
• [9] Enhancing the anti-ageing capacity of hUC-MSCs via NMN co-treatment in D-galactose-induced ageing mice and cellular senescence models — https://pubmed.ncbi.nlm.nih.gov/42520895/
• [10] Irisin in the aging immune landscape: A new player at the crossroads of immunosenescence and sepsis — https://pubmed.ncbi.nlm.nih.gov/42425420/