The number of people aged 100 or older is rapidly increasing: in 2024, it reached approximately 722,000 and is expected to reach 4 million by mid-century. The highest numbers are observed in Asia, particularly in Japan. In Europe, the number may rise from 96,000 to 500,000 by 2050. Despite this growth, long-lived individuals remain rare.
Women significantly outnumber men among centenarians. In the United States, women account for about 79% of this group. Across countries, the probability of reaching 100 years is several times higher in women than in men: 5.1% versus 1.8%.
A key characteristic of long-lived individuals is their preserved health. Cancer and cardiovascular diseases develop later or not at all. Both are linked to immune dysfunction and chronic inflammation, which can disrupt immune homeostasis and promote disease. Long-lived individuals may also show resistance to autoimmune and infectious diseases, suggesting that their immune system maintains balanced functionality for longer.
To understand these features, researchers analyzed:
- hematopoiesis and thymus function;
- age-related immune changes;
- chronic inflammation and its regulation;
- The gut microbiome role and intestinal barrier.
Hematopoietic System And Thymus
With age, the number of CD34+ progenitor cells declines, but no further reduction is observed in long-lived individuals. Functional properties remain intact: progenitor cells respond effectively to cytokines and form colonies similarly to those in younger individuals. Levels of stem cell factor increase linearly with age.
Clonal hematopoiesis of indeterminate potential is associated with more than a tenfold increase in the risk of hematologic malignancies and cardiovascular disease. In long-lived individuals, clonal hematopoiesis is less pronounced. People over 105 years show lower mutational burden, especially in the ASXL1 and DNMT3A genes. These features are associated with more efficient DNA repair and may contribute to healthy longevity.
The thymus undergoes marked involution, affecting T-cell composition. In most long-lived individuals (84%), naïve T cells are nearly absent, while central and effector memory T cells are increased. The number of terminally differentiated cells remains comparable to that of younger age groups.
Age-Related Changes In The Immune System
Immune aging is associated with increased susceptibility to infections, reduced vaccine efficacy, higher rates of autoimmune diseases, and impaired cancer surveillance.
Immunosenescence involves a shift in immune cell composition – an increase in myeloid cells and a decrease in lymphoid cells, reflecting in reduced thymic output and changes in bone marrow hematopoiesis.
Naïve CD4+ and CD8+ T cells decline, while effector and memory populations increase. Signs of T-cell exhaustion accumulate, and proliferative capacity decreases. In some elderly individuals, especially with chronic cytomegalovirus infection, there is expansion of highly differentiated CD8+CD28− T cells, while CD4+ T cells decline. This imbalance may form a high-risk immune profile associated with increased mortality.
γδ T cells decrease in number but largely retain function, contributing to antimicrobial defense, cancer surveillance, and inflammation regulation.
B cells show reduced diversity and accumulate somatic mutations, potentially decreasing antibody diversity and increasing leukemia risk.
Innate immunity also ages: NK cell numbers are often preserved, but cytotoxic activity declines.
In long-lived individuals, some of these changes are less pronounced or compensated for to maintain immune competence.
Innate Immunity In Long-Lived Individuals
Complement system. Function is largely preserved, with increased levels of proteins involved in both activation and regulation of inflammation, supporting the idea that precise modulation of complement pathways contributes to immune resilience.
Neutrophils. These cells constitute 40–70% of leukocytes and play a central role in defense. In long-lived individuals, granulocyte numbers increase, with enhanced phagocytosis and cytokine production, but reduced superoxide generation. Unlike middle-aged individuals, whose neutrophils show dysfunction, those in long-lived individuals resemble those of younger adults. High antioxidant activity – including catalase and glutathione levels – may contribute to a longer, healthier lifespan.
NK cells. Their number may increase, and their cytotoxicity and cytokine production remain comparable to those of younger individuals, supporting tumor surveillance and tissue homeostasis.
Adaptive Immunity In Long-Lived Individuals
B and T cells. Total CD4+ T cells and lymphocytes are reduced, including CD8+ T and B cells. However, long-lived individuals lack the proinflammatory shift typical of aging. Despite fewer naïve T cells, there is an increase in terminally differentiated memory cells (TEMRA), reflecting adaptive compensation. They also show higher proportions of naïve CD8+ T cells and lower proportions of cytotoxic and CD4+ memory cells. Cells with high ribosomal activity are enriched, associated with lower inflammation and slower aging.
γδ T cells. Their number is reduced, mainly due to fewer Vδ2+ cells. Function is partially preserved, with increased TNF production and maintained cytotoxicity, though proliferation declines and susceptibility to apoptosis increases.
Overall, these changes reflect compensatory remodeling shaped by lifelong antigen exposure, including persistent viral infections such as cytomegalovirus.
Autophagy And Apoptosis
Reduced autophagy contributes to T-cell dysfunction with aging, but long-lived individuals show partial preservation of autophagy. Activity of autophagy-related genes and proteins, including Beclin-1, is increased, while inhibitors are reduced. Enhanced autophagy lowers aging markers in vitro.
Balance between pro- and anti-apoptotic molecules (FAS/FASL) is maintained, supporting immune function.
However, findings are mixed: in some long-lived individuals, autophagy declines, while in their offspring it is better preserved, suggesting a delayed, but not prevented, decline.
Chronic Inflammation And Its Regulation
Inflammaging arises from stressors, including:
- cellular senescence;
- mitochondrial dysfunction;
- DNA damage;
- gut dysbiosis;
- accumulation of damage-associated molecular patterns.
Cellular debris acts as a постоянный stimulus for innate immune activation.
Long-lived individuals often exhibit elevated levels of inflammatory markers, including CRP, IL-6, TNF, and IFN-γ. However, health can remain preserved. The key factor is not absolute cytokine levels but the balance between pro- and anti-inflammatory signals.
Healthy, long-lived individuals maintain Treg activity, elevated anti-inflammatory mediators, and higher CD4+/CD8+ ratios, thereby avoiding a high-risk immune profile.
At the molecular level, inflammation is better controlled: reduced NLRP3 activity, preserved autophagy, less DNA damage, and fewer RNA:DNA hybrids. These mechanisms limit the pathological consequences of chronic immune activation.
Role Of The Gut Microbiome And Intestinal Barrier
Age-related microbiome changes include:
- reduced diversity;
- increased instability;
- loss of beneficial bacteria (Clostridiales, Bifidobacterium);
- overrepresentation of Proteobacteria, including Escherichia and Klebsiella.
These changes reduce short-chain fatty acid production and essential amino acid synthesis, promoting inflammation and disease susceptibility.
In contrast, long-lived individuals have a microbiome resembling a younger state – diverse, stable, enriched in beneficial bacteria such as Bifidobacterium and Akkermansia, with fewer pathogens.
Functionally, their microbiome produces metabolites that regulate immunity and reduce inflammation. Japanese centenarians also harbor microbes producing unique secondary bile acids with strong antimicrobial activity.
Diet plays a key role: diverse, predominantly plant-based diets are associated with healthy microbiome profiles during aging. Typical habits include moderate, regular eating without overeating or undereating, supporting circadian rhythms, and immune balance.
Experimental data support the role of microbiota: depletion in aged mice reduces inflammatory gene expression, while transplantation from young mice restores barrier integrity and reduces inflammation. Oral administration of Akkermansia improves barrier function and extends lifespan in accelerated aging models.
Maintaining intestinal barrier integrity is crucial. Long-lived individuals show lower levels of markers of permeability and endotoxemia – zonulin and LPS – compared with both diseased and healthy younger individuals.
Overall, these findings indicate preservation of the gut–immune axis in long-lived individuals, supporting the control of inflammation and resistance to disease.
Reference
The long-lived immune system of centenarians
