A null mutation in SERPINE1 protects against biological aging in humans

Area of Science:

• Genetics
• Gerontology
• Metabolism

Background:

• Plasminogen activator inhibitor-1 (PAI-1) is implicated in cellular senescence and aging.
• While PAI-1 deficiency benefits aging in mice, its role in human longevity is unknown.

Purpose of the Study:

• To investigate the role of a rare loss-of-function mutation in SERPINE1 (encoding PAI-1) in human longevity and metabolism.

Main Methods:

• Studied 177 members of the Berne Amish community, including 43 carriers of the null SERPINE1 mutation.
• Analyzed associations between the mutation and traits like telomere length, insulin levels, diabetes prevalence, and lifespan.

Main Results:

• Carriers of the null SERPINE1 mutation exhibited significantly longer leukocyte telomere length.
• Heterozygosity was associated with lower fasting insulin levels and reduced diabetes mellitus prevalence.
• The null SERPINE1 allele carriers demonstrated a longer lifespan within the Amish kindred.

Conclusions:

• PAI-1 has a causal effect on human longevity, potentially mediated by metabolic alterations.
• Studying loss-of-function mutations in isolated populations offers insights into aging.
• PAI-1 presents a novel therapeutic target for interventions against aging.