Impetus Grants Seeks an LDL Cholesterol for Aging, a Marker That Could Speed Up Drug Testing

Impetus Grants Seeks an LDL Cholesterol for Aging, a Marker That Could Speed Up Drug Testing

On September 24, Norn Group announced that its Impetus Grants program is funding three lines of research: finding a better way to measure biological age, learning to distinguish its harmful components from protective ones, and making the measurement affordable for large trials. In Norn Group's framing, this amounts to a search for a surrogate biomarker, one that can indicate in advance whether a treatment will improve health.

LDL cholesterol serves this role in cardiology: a reduction in its level can be used to assess a drug's cardiovascular benefit without waiting for heart attacks, strokes, or deaths. No such recognized marker exists for aging yet. The FDA has granted such status only once, in December 2025, for osteoporosis, based on bone mineral density. In Norn Group's announcement, three already published studies form a single chain: choosing what exactly to measure, understanding what a change in that measure means, and making the measurement cheap enough for large-scale studies.

The first link in the chain, choosing what to measure, is addressed by Raghav Segal and colleagues. They compared 16 epigenetic clocks (algorithms that estimate age from DNA methylation, that is, from chemical marks on DNA) across 51 human intervention studies. Whether a clock's response to such interventions proves its value as a surrogate is a question that critics have already challenged. Another study by the same group, Systems Age, produces separate age estimates for 11 organ systems from a single blood sample: according to the authors, each system-specific estimate predicts the corresponding diseases and signs of aging more accurately than an overall score.

The second link, what a shift in the marker actually means, is addressed by Vadim Gladyshev's group. They used Mendelian randomization, a genetic method for causal inference, to identify methylation sites that may be causally linked to healthy lifespan. After testing seven existing clocks, they found that those clocks rely on almost none of these sites. On this basis, the group built DamAge and AdaptAge: the first captures signals of age-related damage, the second captures signals of the body's protective adaptation. The same shift in a clock can mean different things: what matters is whether harmful or protective signals dominate.

The third link in the chain is scale. TIME-seq, a method developed by Patrick Griffin's team, allows many samples to be prepared and sequenced together; in large experiments, the authors estimated a roughly 100-fold reduction in the cost of methylation analysis. The method was validated on more than 1 800 mouse DNA samples from eight tissue and cell types, and a human blood clock was trained and tested on 1 056 samples: in the test set, the median age-prediction error was 3.39 years.

The problem itself was articulated in 2023 by the Aging Biomarkers Consortium: a reliable aging marker still lacks both standards and agreed-upon criteria. The last author of that paper, and a co-author on two of the three studies described here (DamAge/AdaptAge and TIME-seq), is the same scientist, Vadim Gladyshev. Whether this reflects a deliberate strategy of his laboratory or simply the dynamics of a small field, where the same groups shape the methodology for measuring aging, is an open question. Epigenetic clocks share a common weakness: they are reasonably good at ranking who is older, but less reliable at showing whether a treatment has worked. A different approach to this weakness comes from the U.S. agency ARPA-H, whose THRIVE coalition is building a methylation-free aging measure based on functional tests and data from wearable devices.