Chronic inflammation is a feature of aging, the constant inappropriate overactivation of the immune system. Many of the mechanisms that contribute to this unfortunate state are catalogued and understood to at least some degree, such as growing numbers of senescent cells, excess visceral fat tissue, numerous forms of molecular damage and debris that are interpreted as cues for immune activation, and so forth. While short-term inflammation is necessary to maintain tissue, respond to pathogens, and heal injuries, when unresolved that same signaling and changed cell behavior is very disruptive of tissue maintenance and function. Greater inflammation leads to worse outcomes over time, a more rapid onset and progression of all of the common age-related conditions. Suppression of chronic inflammation, preferably by cleaning up the damage that causes the immune system to respond in this way, is an important goal in the treatment of aging as a medical condition.

The biological bases of longevity are not well understood, and there are limited biomarkers for the prediction of long life. We used a high-throughput, discovery-based proteomics approach to identify serum peptides and proteins that were associated with the attainment of longevity in a longitudinal study of community-dwelling men age ≥65 years. Baseline serum in 1196 men were analyzed using liquid chromatography – ion mobility – mass spectrometry, and lifespan was determined during ~12 years of follow-up. Men who achieved longevity (≥90% expected survival) were compared to those who died earlier.

Rigorous statistical methods that controlled for false positivity were utilized to identify 25 proteins that were associated with longevity. All these proteins were in lower abundance in long-lived men and included a variety involved in inflammation or complement activation. Lower levels of longevity-associated proteins were also associated with better health status, but as time to death shortened, levels of these proteins increased. Pathway analyses implicated a number of compounds as important upstream regulators of the proteins and implicated shared networks that underlie the observed associations with longevity.

Overall, these results suggest that complex pathways, prominently including inflammation, are linked to the likelihood of attaining longevity. This work may serve to identify novel biomarkers for longevity and to understand the biology underlying lifespan.