How Immunosenescence Changes with Age
Immunosenescence is the age-related decline of immune function, marked by thymic involution, reduced T-cell output, chronic low-grade inflammation, and expansion of senescent immune cell subsets. This page reviews the me
Immunosenescence is the formal term for the progressive, age-associated deterioration of immune function. It is also referred to in the literature as age-related immune decline or immune ageing, and it is best understood not as a single defect but as a class of coordinated changes spanning both innate and adaptive immunity. The defining features reported across studies include thymic involution, reduced T-cell production, chronic low-grade inflammation, telomere shortening, and the expansion of senescent immune cell subsets [1][2]. Because immunosenescence is a process rather than a molecule, it has no sequence, formula, or molecular weight; the identifiers that recur in the literature are functional and cellular — thymic output, circulating cytokine profiles, and the proportion of senescent T-cell populations [1][2].
The work in this area centres on thymic output and T-cell differentiation as the primary axis, with the thymus as the organ whose age-related shrinkage is treated as the initiating event in the decline [2].
Research Studies
Thymosin alpha-1 and thymic output in aged subjects
Thymosin alpha-1 (Tα1) is a peptide hormone produced by the thymus. In the reviewed literature it is described as exhibiting immunomodulatory, anti-inflammatory, and antioxidant properties, and as acting by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity [2]. Preclinical and clinical studies cited in that review report that Tα1 improved vaccine response in elderly subjects and mitigated features of immunosenescence [2]. The same review notes work on a hybrid drug, Refnot, described as a fusion construct [2].
Thymosin alpha-1 and immunosenescence in stage I NSCLC
A registered trial has been designed to explore the effect of thymosin alpha-1 on postoperative peripheral blood circulating tumour cells and on immunosenescence in patients with early-stage non-small cell lung cancer [4]. This is a disease-population study; the population is patients with stage I NSCLC, and the outcomes of interest are circulating tumour cells and immunosenescence markers [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 people with metabolic disorders, with the stated aim of providing a new method to address immunosenescence [3]. The same study examined effects of NMN supplementation on glucose and lipid metabolism [3]. The population here is middle-aged and elderly individuals with metabolic disorders, and the design is placebo-controlled [3].
Nicotinamide mononucleotide and mesenchymal stem cell senescence in mice and cell models
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been studied as an anti-ageing approach, but the ageing microenvironment can induce oxidative stress and senescence in transplanted hUC-MSCs, impairing their capacity to delay immunosenescence [9]. Work in this area has examined enhancing the anti-ageing capacity of hUC-MSCs via NMN co-treatment 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, and it invokes a large surgical stress response — systemic epinephrine rising 33-fold and norepinephrine rising 3-fold [5]. Local tissue injury produces sterile inflammation with release of damage-associated molecular patterns, which activate neutrophils and drive cascades of cytokines, complement, and coagulation changes; nociceptor activation produces a neurometabolic response involving the sympathetic nervous system and the hypothalamus-pituitary axis [5]. A registered trial, AEGIS, examines alpha-ketoglutarate for geroprotection in this surgical setting [5].
Taxifolin and ergothioneine and immune biomarkers in healthy volunteers
Measuring the impact of dietary interventions on immune function is complicated by the responsiveness of the immune system to environmental influences including diet, which supplies the energy for a protective immune response and the building blocks for mediators such as antibodies and cytokines, and can act indirectly through the gut microbiome [6]. 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 [6]. The TaxEr study examined taxifolin and ergothioneine against immune biomarkers in healthy volunteers [6].
Immunosenescence in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune dysregulation across the lifespan, and accumulating evidence indicates that many immunological alterations in SLE resemble those of physiological ageing [1]. The mechanisms reviewed include telomere shortening, chronic low-grade inflammation, thymic dysfunction, and expansion of senescent immune cell subsets, with these age-associated immune phenotypes emerging early and contributing to disease activity, organ damage, and long-term outcomes [1]. Clinically, immunosenescence in this context has been linked to cardiovascular complications [1].
Irisin and the ageing immune landscape
Irisin is a muscle-secreted myokine induced by exercise and has been described as a molecular bridge between muscle activity and the immune system [10]. In ageing, irisin may modulate the transition toward immunosenescence and influence host vulnerability to acute systemic inflammation [10]. This evidence is reviewed at the level of mechanism and does not establish a clinical outcome.
Bone immunity and age-related bone disease
Bone metabolism is regulated by immune cells that maintain skeletal homeostasis through cytokine secretion and cell interactions, and disruption of this regulation by inflammation, autoimmunity, or ageing drives pathological bone diseases including osteoporosis and rheumatoid arthritis [8]. Single-cell technologies are noted in this literature as tools for resolving the relevant cell populations [8].
Comparison of research models and populations
| Compound or axis | Model or population | Reported focus |
|---|---|---|
| Thymosin alpha-1 | Elderly subjects; preclinical models [2] | Vaccine response, thymic output, T-cell differentiation [2] |
| Thymosin alpha-1 | Stage I NSCLC patients [4] | Circulating tumour cells, immunosenescence [4] |
| Nicotinamide mononucleotide | Middle-aged and elderly with metabolic disorders [3] | Immunosenescence, glucose and lipid metabolism [3] |
| Nicotinamide mononucleotide | D-galactose-induced ageing mice; cell models [9] | hUC-MSC senescence and immunosenescence [9] |
| Alpha-ketoglutarate | Older CABG patients [5] | Surgical stress response, geroprotection [5] |
| Taxifolin and ergothioneine | Healthy volunteers [6] | Immune biomarkers [6] |
| Irisin | Ageing immune landscape (review) [10] | Immunosenescence and sepsis vulnerability [10] |
Menopause, NAD, and immunosenescence
Menopause is a complex biological condition associated with progressive estrogen depletion and increased susceptibility to several age-associated disorders, and the mechanisms implicated include mitochondrial dysfunction, oxidative stress, chronic inflammation, genomic instability, and immunosenescence [7]. This is a review-level association and does not establish that any intervention alters the trajectory.
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Sources
- [1] Immunosenescence in systemic lupus erythematosus: Mechanisms, clinical consequences, and therapeutic implications
- [2] Aging and Thymosin Alpha-1
- [3] The Impact of Nicotinamide Mononucleotide Sustained-release Tablets on Immunosenescence and Metablism in Middle-aged and Elderly Individuals With Metabolic Disorders
- [4] Immuno-effect of Tα1 for Stage I NSCLC
- [5] Alpha Ketoglutarate Enhances Geroprotection In Surgery (AEGIS)
- [6] Taxifolin/Ergothioneine and Immune Biomarkers in Healthy Volunteers (TaxEr)
- [7] Nicotinamide Adenine Dinucleotide and Its Anti-aging Effects in the Context of Longevity and Menopause
- [8] Advances in the study of the role of bone immunity in physiological and pathological processes related to bone metabolism
- [9] Enhancing the anti-ageing capacity of hUC-MSCs via NMN co-treatment in D-galactose-induced ageing mice and cellular senescence models
- [10] Irisin in the aging immune landscape: A new player at the crossroads of immunosenescence and sepsis