Our projects arose from our long-term efforts to identify interventions that promote healthy aging. Some biological processes that are essential early in life might be harmful as we age. A good example is cell proliferation. You need a lot of it after you are born to grow into an adult or when you are pregnant to develop a fetus. But when you are old, too much cell proliferation leads to many chronic diseases, such as rheumatoid arthritis (RA) or, worse, cancer. Proliferating cells need folate, a vitamin. Antifolate drugs treat RA and cancer. On the other hand, to help children and pregnant women, the US and other countries fortify staple foods with folate.

But is it possible that older individuals who need less cell proliferation also need lower folate in their diet? We asked that question and showed that reducing dietary folate in mid-life mice altered metabolism and reduced markers of cellular proliferation and aging-related decline (PMID: 39043420). We are developing new compounds to mimic these effects by blocking intestinal folate uptake. This approach offers a non-dietary intervention to limit folate levels, with much lower systemic exposure, and side-effects, than classic antifolates.