Flu shots work in 70% to 90% of younger adults. In people over 65 the range falls to 17% to 53%. That gap is the clearest bill that immunosenescence, the slow wearing-out of immune defences with age, hands to the health system.
The figures come from an April 2025 review by Tommy C. Sim, which also puts the stakes in economic terms. The number of people over 60 is projected to double by 2050. In the United States, annual healthcare spending for people over 65 is three times higher than for younger adults, and the review expects global aging-related health spending to rise by over 30% by 2050 without effective intervention.
Where the machinery breaks
The mechanics here start with the thymus, the organ that develops T cells. As it shrinks with age, it makes fewer naive T cells, the ones that meet new pathogens for the first time. A Frontiers in Immunology review ties the weak vaccine response in part to defective T cell memory, pointing to lost proliferative capacity and reduced receptor function and diversity.
Other parts of the system slip too. Natural killer cells kill less effectively and macrophages swallow fewer pathogens. B cells, which make antibodies, work less well, so antibodies after a shot come in smaller quantities and are lower in quality. Antigen-presenting cells spot invaders more slowly. Layered on top is chronic, low-grade inflammation, nicknamed inflammaging, with raised IL-6, TNF-alpha and C-reactive protein. The catch, according to the review, is that this persistent inflammation also damages tissue and feeds cardiovascular disease and neurodegeneration.
The Frontiers authors add something less obvious. Inflammaging itself appears to blunt vaccine response. Yet most efforts to improve immunogenicity in the elderly have relied on adjuvants that trigger local inflammation, which they call a seeming paradox. Higher doses and alternative routes of vaccination, they write, have shown only limited benefits.
Who dies
Despite widespread vaccination, people in older age groups make up more than 80% of deaths from illnesses a vaccine can prevent, like influenza and pneumonia, the Sim review says. The weak response extends to pneumococcal, shingles and COVID-19 vaccines. One workaround is revaccination: boosters of COVID-19 mRNA vaccines have been shown to restore neutralizing antibody levels and improve efficacy in people 65 and older.
What is being tried
Researchers are testing ways to repair the system rather than just prod it. Thymic rejuvenation is one line. A natural peptide called thymosin alpha-1 has shown promise in stimulating thymic activity and T cell production, while preclinical work suggests fibroblast growth factor 7 may help the thymus regenerate. Caloric restriction and exercise are linked to slower thymic atrophy.
Stem cell transplants are a second line, replacing aged immune cells with a new pool. The price is the obstacle: roughly $100,000 to $200,000 per patient and specialized facilities. A third is CAR T-cell therapy, built for cancer and now being adapted in preclinical studies to target cytomegalovirus. It remains experimental for aging.
The cheapest option is also the oldest. The review says moderate aerobic activity, such as brisk walking for 30 minutes five times a week, can improve vaccine responses by up to 50%.
Sources
- Aging and Immunity: Challenges, Insights and Breakthrough Solutions
- Aging and Immunity (continued): impaired vaccine response
- Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly (Frontiers in Immunology)
- Aging and Immunity (continued): potential solutions
