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Chronic low-grade inflammation (inflammaging) progresses with aging. Inflammatory markers such as IL-6, CRP, and TNF-α increase with age and are associated with an increased risk of cancer, cardiovascular disease, and mortality.
Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein that plays a role in tissue homeostasis by promoting adaptive inflammation and subsequent tissue remodeling. However, excessive ANGPTL2 secretion induced by unhealthy lifestyle factors, such as excessive caloric intake and lack of exercise, can lead to maladaptive chronic inflammation and irreversible pathological tissue remodeling, thereby accelerating the development of cancer, atherosclerosis, and metabolic syndrome.
Circulating ANGPTL2 levels have been reported to be associated with the risk of developing diseases such as diabetes and cardiovascular disease; however, the association with mortality in community-dwelling populations has not been fully investigated.

A research group led by Dr. Akiko Tamakoshi (Department of Public Health, Faculty of Medicine, Hokkaido University) conducted a study in community-dwelling Japanese populations to investigate the association between plasma ANGPTL2 levels and mortality risk.

This study is a case–cohort study based on the New Integrated Suburban Seniority Investigation (NISSIN) project. Plasma ANGPTL2 levels were measured using ELISA, and statistical analyses were performed using Cox proportional hazards models, adjusting for numerous confounding factors, including sex, lifestyle habits, medical history, BMI, and inflammatory markers (hs-CRP).

Study population
  Baseline participants: 3,073 (age 64 years)
  Sub-cohort: 714 (randomly selected)
  Death cases: 387
  Follow-up period: up to 20 years (through 2015)

Key Findings
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Baseline characteristics
- Plasma ANGPTL2 levels were significantly higher in fatal cases than in the sub-cohort.
- Inflammatory and metabolic markers, such as hs-CRP and uric acid, were also elevated.

Association with all-cause mortality
- The group with the highest plasma ANGPTL2 levels (fourth quartile) showed
  a significantly higher risk than the lowest quartile.
- All-cause mortality risk: approximately 1.86-fold (HR 1.86, 95% CI 1.22–2.83)
- This association remained significant after multivariable adjustment, including hs-CRP.

Association with cancer mortality
- Higher ANGPTL2 levels were significantly associated with increased cancer mortality risk.
- Approximately 2.08-fold increase (HR 2.08, 95% CI 1.24–3.50)

Association with non-cancer mortality
- No statistically significant association was observed in the fully adjusted model;
  however, a positive trend was noted with increasing ANGPTL2 levels.

Subgroup analyses (smoking, alcohol consumption, frailty)
- No statistically significant interactions were observed between subgroups.
- Positive associations between ANGPTL2 levels and mortality risk were observed
  within each group.
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ANGPTL2 is one of the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells. This study suggests that elevated circulating ANGPTL2 levels may reflect accelerated aging and chronic inflammatory status and are associated with increased mortality risk. Notably, the association remained significant even after adjustment for hs-CRP, suggesting that ANGPTL2 may capture biological information distinct from conventional inflammatory markers. ANGPTL2 has also been reported to be involved in tumor proliferation, metastasis, and the formation of a pro-inflammatory tumor microenvironment. The observed association with cancer mortality in this study is consistent with these findings.

This study is the first to report that plasma ANGPTL2 levels are independently associated with mortality risk, particularly cancer mortality, in a community-dwelling population of younger-old adults. These findings suggest that ANGPTL2 may serve as a potential biomarker reflecting chronic inflammation and aging. Elevated plasma ANGPTL2 levels were significantly associated with increased mortality risk, and further validation studies are expected to support its potential application in risk stratification for future disease onset and prognosis.

Please refer to the following publication for more details.

Wenjing Zhao et al.
Plasma Angiopoietin-Like Protein 2 Levels and Mortality Risk Among Younger-Old Japanese People: A Population-Based Case-Cohort Study
J Gerontol A Biol Sci Med Sci. 2022; 77(6):1150-1158.

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