ApoD May Explain Severe Flu in Older Adults, Guide Future Pharmacy Care

Influenza (flu) remains a serious threat to older adults. According to the National Institute on Aging (NIA), contracting flu can be very serious and possibly life-threatening for older adults, especially those with chronic underlying health conditions. Not only are patients aged 65 and older at risk of serious complications in case of infection, but they also account for a disproportionate share of flu-related hospitalizations and deaths, even in seasons when vaccine uptake is moderate.^1,2

ApoD and Age-Associated Susceptibility

A recent study published in the Proceedings of the National Academy of Sciences has identified that apolipoprotein D (ApoD), which is a glycosylated lipid-binding protein, is found in the lungs of older individuals in high concentrations and can suppress the antiviral immune response during influenza infection.³ Through aged mouse models and human donor lung tissue, the researchers showed that high ApoD levels cause cellular power plant destruction (through mitophagy) that weakens the interferon type I signaling and enables greater viral replication and tissue damage.³ The researchers suggest that ApoD, as a possible drug target, could help reduce the severity of influenza in the elderly.²

Understanding this mechanism bridges the gap between observational epidemiology and possible interventions. In that sense, it is known that an aging immune system and chronic inflammation are important factors towards weakened immunity in older adults. However, the precise molecular factors that have a direct negative impact on antiviral defenses have remained unknown. ApoD introduces a possible “druggable” node that could complement existing preventive strategies.³

Vaccine Limitations in Older Adults

A systematic review of global data reveals that individuals aged 65 and older are at elevated risk of hospitalization, requiring intensive care, and mortality, even in settings with high vaccine rates.³ The review highlights that although there is large-scale influenza vaccination, considerable clinical burden linked to influenza continues, and vaccine effectiveness needs to be enhanced.³ The aggravation of increased burden is supported by the presence of other diseases (eg, heart disease, chronic lung disease, and diabetes) and the diminished ability of the immune system in older individuals.³

Older adults are usually less responsive to standard-dose vaccines, and their antibodies also decline faster. To help combat this problem, the CDC and vaccine advisory committees are currently recommending that individuals over 65 should receive a higher-dose or an adjuvanted influenza vaccine.¹ The NIA states that “there are flu shots tailored just for seniors,” and that the strengthened vaccines ”give a more powerful immune reaction.”¹ Additionally, the results of vaccine effectiveness confirm that the extent of the protection depends on the season, the compatibility of the strain, and the age group under consideration.³

Even with enhanced vaccines, however, breakthrough infections and severe disease still occur. Hence, adjunctive approaches—such as therapies targeting molecular vulnerabilities like ApoD—could add value, particularly among high-risk older patients.²^,³

Challenges and Looking Ahead

The results related to ApoD are encouraging. However, there are still numerous obstacles to overcome before these findings can be converted to clinical application. Among the complexities are the creation of safe and selective ApoD inhibitors, the delivery of these inhibitors effectively to the lungs, and testing their effectiveness in humans. Special attention will have to be given to the safety of older patients who are usually on multiple medications. In addition, since the ApoD route is just one aspect of the quiver of frailty, combinatorial approaches will likely be necessary.³

From a public health perspective, improving vaccine match fidelity, exploring novel platforms, and enhancing uptake remain priorities. Pharmacists can play a key role in all these domains by promoting vaccination, counseling patients, and staying current on emerging therapies.¹

REFERENCES

1. National Institute on Aging. Flu and Older Adults. National Institutes of Health. https://www.nia.nih.gov/health/flu/flu-and-older-adults. Accessed October 2, 2025.

2. EurekAlert. Scientists discover why older people are more likely to suffer severely from the flu. September 30, 2025. https://www.eurekalert.org/news-releases/1097051.

3. Jiang Z, et al. ApoD mediates age-associated increase in vulnerability to influenza virus infection. Proc Natl Acad Sci USA. 2025;122(41):e2423973122. doi:10.1073/pnas.2423973122.