Aging is a loss of flexibility.

Two conserved kinases, AMPK and mTORC1, read a cell’s energy and nutrient state and decide how it responds. We study how they work together to keep metabolism flexible, and how that coordination fails with age.

Will’s postdoctoral work showed that AMPK extends lifespan through the CRTC/CREB transcriptional switch. In our lab, we found that this signal acts from neurons to reprogram metabolism and longevity across the whole body. We also showed that inhibiting mTORC1 in neurons alone can extend life without the costs to growth and reproduction that usually accompany it. Today we are mapping how nutrient cues reach mTORC1 through the Rheb–GATOR1 machinery, and how AMPK and mTORC1 together mediate the benefits of dietary restriction and intermittent fasting.

Switching between fuels takes physical change. Mitochondria fuse and fragment, peroxisomes multiply, and organelles talk to one another. We study this remodeling as the cellular hardware of metabolic flexibility.

We found that dietary restriction and AMPK extend lifespan only if mitochondrial networks stay dynamic and peroxisomes can respond alongside them. ER-to-mitochondria calcium signaling links stress responses to longevity, and mitochondria form nutrient-responsive derived structures. Most recently we described a peroxisome-led inter-organelle cascade that orchestrates metabolic flexibility and longevity. We are now asking how this remodeling is lost with age.

Flexibility is also written in how genes are read. We were the first to show that RNA splicing factors causally regulate aging.

Splicing factor 1 is required for dietary restriction and reduced TORC1 signaling to extend life, and the early-life activity of splicing factors determines how well longevity interventions work later on. We have also found that chromatin modifiers act through CRTC-1, and, with the Brunet lab, that lipid droplets and peroxisomes are co-regulated to extend lifespan. Together these results connect gene regulation to lipid metabolism and long-term health.

Interventions such as dietary restriction slow aging in almost every organism, but not equally in every individual. We want to know who will benefit, and why.

Our 2020 commentary with Maria Perez-Matos, “A stepping stone toward precision geroscience”, is, to our knowledge, the earliest use of the term “precision geroscience” in the indexed biomedical literature (PubMed and Europe PMC).

We are building biomarkers that predict an individual’s response to pro-longevity interventions. One example is endogenous mitochondrial NAD(P)H, which can forecast lifespan. With collaborators, we are testing whether age-related changes in redox signaling are regulated rather than random, mapping how dietary restriction reshapes them in mice. We are also asking whether keeping neurons metabolically flexible protects against Alzheimer’s disease. Through the Harvard Chan Healthy Aging Initiative, we connect this biology to measures of biological age in people and to equity in who gets to age well.