A massive human genetics study identified rare folliculin-interacting protein 1 (FNIP1) mutations associated with favorable metabolism and much lower cardiometabolic disease risk. Experiments in human liver cells and mice suggest a therapeutic route [1].
Longevity hidden in the genome
For decades, aging researchers have hoped that human genetics might reveal genuine “longevity genes” whose altered activity produces substantially healthier or longer lives and therefore provides an obvious therapeutic target. However, unlike in some simpler organisms, human aging seems to be highly influenced by numerous genes (polygenic), most of which have relatively small effects. The APOE gene, strongly associated with dementia, might count as an exception, as well as FOXO3, although the latter’s effect is not nearly as strong.
Importantly, that does not necessarily mean that genetics contributes little to lifespan. Some recent research argues that intrinsic human lifespan may be highly heritable while still being genetically complex [2]. Although these results are still a matter of active debate, there is no denying that our genes do affect our lifespan.
In a new study coming from the biotech company Regeneron and published in Nature, the researchers leveraged 11 large cohorts to analyze the protein-coding parts of the genome (the exomes) of more than one million people with extensive linked health and phenotype data.
60% risk reduction
The team focused on energy metabolism because metabolic dysfunction contributes to obesity, type 2 diabetes, cardiovascular disease, and metabolic-dysfunction-associated steatotic liver disease (MASLD). Rather than starting with one candidate gene, they used the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL) as a marker of metabolic state and searched for genetic variants associated with unusually high or low values.
The authors’ bet was that TG:HDL genuinely captures something meaningful about whole-body energy metabolism, and their analysis using a remarkably broad set of metabolic measurements confirmed that: a higher TG:HDL consistently tracked a worse metabolic phenotype. Importantly, this was not just cross-sectional but also longitudinal. People with higher baseline TG:HDL subsequently had higher rates of type 2 diabetes, myocardial infarction, MASLD, and cirrhosis. The relationships appeared across several ancestry groups.
Analyzing their one-million-strong dataset, the researchers found 59 genes in which rare protein-altering variants had independent, statistically robust effects on TG:HDL. Only 15 had been identified in the previous largest rare-variant TG:HDL analysis, meaning that 44 were new associations.
The 59 genes were strongly enriched for genes expressed in the liver and adipose tissue, the organs that govern lipid storage and energy metabolism. Many belonged to familiar pathways. 31 of the 59 encode known drug targets, and 23 are already targeted by approved drugs or agents in human clinical development – an encouraging sign that their genetic screen was picking up biologically and therapeutically relevant pathways.
People carrying ultra-rare loss-of-function mutations in one copy of the gene FNIP1 had much lower TG:HDL and one of the strongest favorable metabolic signatures in the entire study: the carriers had lower triglycerides and ApoB, less liver fat, better glycemic control, and a more favorable distribution of body fat.
Most importantly, heterozygous FNIP1 loss-of-function carriers had about 60% lower odds of a composite cardiometabolic disease outcome, which consisted of coronary artery disease (CAD), type 2 diabetes, MASLD, and cirrhosis. However, the estimate was based on relatively few mutation carriers, and the reductions in CAD and cirrhosis individually did not reach statistical significance.
“This study implicates the FNIP1 pathway in human energy metabolism and in the risk of common cardiometabolic diseases in the general population,” said Dr. Luca Andrea Lotta, Head of Cardiometabolic and Musculoskeletal Disease Genetics at the Regeneron Genetics Center and the study’s corresponding author, to Lifespan News. “It illustrates the power of large-scale human genetics to reveal new and important biology and identifies a pathway that may be modified for therapeutic benefit in these common diseases.”
A metabolic break
The next question was about why having one defective copy of FNIP1 would produce such a phenotype. FNIP1 partners with folliculin (FLCN) in a nutrient-sensing pathway downstream of AMPK, one of the cell’s central sensors of energy availability. Previous work suggested that reducing FNIP1/FLCN activity might increase mitochondrial activity, fuel oxidation, and cellular energy expenditure [3].
“The FNIP1 pathway can be considered a ‘metabolic brake,’ curbing the consumption of energy so that calories can be saved for a ‘rainy day’ when we may undergo prolonged fasting/starvation,” said Lotta. “This happened all the time over millennia of human evolution but almost never happens in the modern calorie-rich environment, so this pathway now leads to cardiometabolic diseases, and mutations that switch it off are protective.”
Knocking down FNIP1 in primary human hepatocytes activated a transcriptional program associated with lysosomal activity and lipid breakdown. Disrupting the FNIP1-FLCN pathway specifically in the livers of mice fed a high-fat, high-fructose diet protected against obesity, fatty liver, and insulin resistance. Importantly, however, in mice, the effect hinged on also inhibiting the closely related protein FNIP2. This was not the case in human liver cells. The researchers attribute this discrepancy to inter-species differences, but this might have consequences for clinical translation.
“Developing new medicines is always hard and this makes it more difficult to study this pathway in model organisms and preclinical models, so it adds a layer of complexity,” Lotta said. “However, our human cell experiments suggest that, in humans, silencing of FNIP1 alone should be enough. We are pursuing more testing to better understand the biology of this pathway.”
Literature
[1] Hindy, G., Adam, R. C., Sosina, O., Pryce, D., Blair, D., Herman, J., … & Lotta, L. A. (2026). FNIP1 variants are associated with favourable metabolism in 1 million humans. Nature, 1-10.
[2] Shenhar, B., Pridham, G., De Oliveira, T. L., Raz, N., Yang, Y., Deelen, J., … & Alon, U. (2026). Heritability of intrinsic human life span is about 50% when confounding factors are addressed. Science, 391(6784), 504-510.
[3] Malik, N., Ferreira, B. I., Hollstein, P. E., Curtis, S. D., Trefts, E., Weiser Novak, S., … & Shaw, R. J. (2023). Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Science, 380(6642), eabj5559.
View the article at lifespan.io
