Progeria, or Hutchinson-Gilford syndrome (HGPS), results from a mutation in the LMNA gene. This mutation leads to the production of a toxic protein, progerin, which disrupts the functioning of the cell nucleus. Cells lose their stability, deteriorate more rapidly, and the heart ages prematurely, leading to early death around the age of 12 on average. Currently, only a medicine, the Zokinvy (lonafarnib, Eiger BioPharmaceuticals, Inc.) It is approved by the U.S. Food and Drug Administration (FDA). It helps limit the accumulation of progerin without affecting its production.
A lead for age-related diseases
Recent studies have shown thata gene present in supercentenariansLAV-BPIFB4 was shown to mitigate cardiac damage caused by progeria in mouse models of the disease. When introduced into human cells from progeria patients, LAV-BPIFB4 restored some cellular functions, reducing signs of aging and fibrosis, without decreasing progerin levels. To better understand its mechanism of action, Science and Future interviewed Yan Qiu, a researcher at the Bristol Heart Institute and first author of the article published in the journal Signal Transduction and Targeted Therapy.
Sciences et Avenir: Do you have any hypotheses on the molecular mechanisms by which LAV-BPIFB4 strengthens cellular resilience to progerin toxicity?
Yan Qiu We observed that LAV-BPIFB4 expression did not reduce progerin levels, indicating that progerin is not a direct target of LAV-BPIFB4, at least in fibroblasts. In contrast, we found that LAV-BPIFB4 effectively attenuates several pathological effects downstream of progerin accumulation, including cellular senescence and extracellular deposition of EREG, a molecule linked to inflammation and fibrosis.
These observations confirm previous work suggesting that, while progerin accumulation remains a major target in progeria research, interventions aimed at reducing its downstream consequences may offer therapeutic benefits. We also hypothesized that LAV-BPIFB4 transduction could influence gene activities downstream of the LMNA mutation, which could contribute to its therapeutic effects.
"Exploring this potential must be a priority in future research."
In your opinion, could this longevity gene be combined with existing treatments such as lonafarnib? Could such a combination produce additive or synergistic effects?
We hypothesize that LAV-BPIFB4 and lonafarnib may have synergistic or additive effects when used together, potentially offering greater therapeutic benefits than either treatment alone. We observed that LAV-BPIFB4 treatment resulted in an increase in body weight, an effect not shown by lonafarnib in previous studies. This suggests that LAV-BPIFB4 may act on different or complementary pathways involved in progeria progression, such as microvascular dysfunction, fibrosis, or senescence. Exploring this potential should therefore be a priority in future research.
Apart from progeria, do you plan to test LAV-BPIFB4 in models of normal cardiac aging or other age-related cardiovascular diseases?
Part of this work has already been undertaken by another team, which published its results in the journal Vascular PharmacologyIt appears that LAV-BPIFB4 could be beneficial in age-related cardiovascular disorders such as diabetic cardiomyopathy or myocardial infarction, among others.
English 
French