Blocking PAI-1 may slow down aging
A small group of people with a rare inherited mutation live on average seven years longer than others. They lack a working gene for a protein called PAI-1.
PAI-1 (plasminogen activator inhibitor-1) is a protein that naturally regulates blood clotting and tissue repair. But it also plays a role in cellular senescence: the process by which damaged cells stop dividing but do not die, and instead release harmful substances into their surroundings. As we age, these cells accumulate. The researchers describe PAI-1 as a molecular node linking cellular senescence, chronic inflammation and tissue damage.
The review, published in the journal Cells, describes how PAI-1 is involved in a range of processes that characterise the aging body: organ fibrosis, metabolic dysfunction, impaired immune surveillance and an increased tendency toward blood clots. In this framework, PAI-1 is not just a marker of aging-related pathology but an active contributor to it.
From inherited mutation to medicine
The observation that people with a PAI-1 loss-of-function mutation live longer has driven targeted drug development. Scientists have developed a series of small-molecule inhibitors, including TM5275, TM5441 and TM5614. The latter is now an orally available investigational compound that has been evaluated in clinical studies, including in patients with certain cancers and Covid-19-related lung damage.
Inhibiting PAI-1 through a drug produces a smaller effect than the inherited mutation. A drug is only used for part of a lifespan and does not achieve complete inhibition. This is nonetheless how drug development tends to proceed: first understand what a gene does, then develop a compound that partially replicates it.
Cautious optimism
Preclinical data look promising: less clotting, less fibrosis, reduced inflammatory activity and possibly a reduced influence of senescent cells on their tissue environment. But the authors stress that clinical studies remain limited and that safety questions around long-term use are unresolved. Whether PAI-1 inhibition actually extends human lifespan or healthspan has not yet been demonstrated.