Unveiling the Biological, Immunological Factors Driving Flu Severity in Older Adults

Influenza remains a significant threat to individuals ages 65 and over. These individuals are twice as likely to be hospitalized and have more complications and mortality compared with younger populations. Although a large number of vaccinations are administered, this age group is still the most affected by the flu each year, indicating that there are still some unknown factors about the influence of age on susceptibility and the effectiveness of preventive strategies.

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A study recently summarized in ScienceDaily uncovers a key molecular contributor to severe influenza in older adults: apolipoprotein D (ApoD). This glycoprotein accumulates in lung tissue with age, where it disrupts the body’s innate antiviral defenses by impairing the type I interferon response while simultaneously driving mitochondrial dysfunction and tissue damage.

“Aging is a leading risk factor in influenza-related deaths. Furthermore, the global population is aging at an unprecedented rate in human history, posing major issues for healthcare and the economy. So, we need to find out why older patients often suffer more severely from influenza virus infection,” Kin-Chow Chang, a professor at the University of Nottingham, explained.“There is now an exciting opportunity to therapeutically ameliorate disease severity of the elderly from influenza virus infection by the inhibitory targeting of ApoD.”¹ This discovery opens a promising avenue for novel treatments aimed at bolstering antiviral resilience in the elderly.

This molecular insight must be understood within the broader context of immunosenescence—the decline of immune function with age, which is an extrinsic factor that both predisposes the organism to infections and reduces the effectiveness of flu vaccines. The review extensively describes the impact of immunosenescence on different immune compartments. Decreased dendritic cell function, declining NK cell and macrophage activity, and lowered antigen presentation capacity are a few of the major contributors to less efficient immune control and increased viral susceptibility in elder patients.² Likewise, humoral immunity gets weaker: the elderly generally have lower rates of seroconversion after vaccination and weaker neutralizing antibody responses, which is consistent with impaired adaptive immune mechanisms.³

The changes in the immune system that come with age have a direct impact on the flu vaccination. Standard-dose inactivated vaccines are less effective in elderly people. The results of the systematic reviews confirm that more immunogenic formulations—such as high-dose, adjuvanted, and recombinant vaccines—elicit stronger immune responses and provide better protection to this group.⁴ A 2024 review in Nature Reviews reports that high-dose vaccines, containing up to 4 times the amount of hemagglutinin antigen, generate significantly higher antibody titers and are associated with notably reduced influenza-related hospitalization and mortality among individuals ages 65 and older.⁵

Together, these findings underscore the need for multifaceted strategies to reduce flu severity in the elderly. Targeting ApoD pharmacologically may offer a way to preserve lung tissue integrity and restore antiviral defenses during infection. Simultaneously, vaccine policy must evolve; high-dose or adjuvanted influenza vaccines should be the standard for older adults, supported by efforts to improve coverage through reduced cost barriers, prescription simplification, and public education.

Such insights allow pharmacists in the clinical pharmacy setting to implement actions of both molecular and public health intervention. Health care professionals have the opportunity to foster the use of high-dose vaccine therapies customized to patients with immunosenescence, as well as being alert to novel therapeutic approaches addressing ApoD. At the same time, health systems should ensure that these enhanced vaccines are accessible and equitably distributed, particularly to older adults with chronic conditions or mobility limitations.

Using new therapeutic targets like ApoD inhibition together with well-planned vaccine strategies provides multiple protections against a severe flu case in elderly people. While molecular innovation may eventually offer new prophylactic or treatment modalities, the most immediate and impactful approach remains improving access to enhanced vaccines and adapting immunization strategies to the realities of aging immune systems.

REFERENCES

1. Why the flu turns deadly for older adults, and how scientists found the cause. ScienceDaily. Published 2025. Accessed September 9, 2025. https://www.sciencedaily.com/releases/2025/09/250908175434.htm

2. Reber AJ, Chirkova T, Kim JH, et al. Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population. Aging Dis. 2012;3(1):68-90.

3. Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immun Ageing. 2019;16:25. Published 2019 Sep 13. doi:10.1186/s12979-019-0164-9

4. Moa A, Kunasekaran M, Akhtar Z, Costantino V, MacIntyre CR. Systematic review of influenza vaccine effectiveness against laboratory-confirmed influenza among older adults living in aged care facilities. Hum Vaccin Immunother. 2023;19(3):2271304. doi:10.1080/21645515.2023.2271304

5. Hou Y, Chen M, Bian Y, et al. Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies. npj Vaccines. 2024;9(1). doi:10.1038/s41541-024-00874-4