Scientists genetically engineered mice to depend on dietary vitamin B3 like humans and for the first time proved by direct experiment that chronic NAD+ deficiency alone wastes bone and muscle, causes cataracts, and shortens lifespan, while a senolytic relieved part of the damage without restoring NAD+
Scientists genetically engineered mice to depend on dietary vitamin B3 like humans and for the first time proved by direct experiment that chronic NAD+ deficiency alone wastes bone and muscle, causes cataracts, and shortens lifespan, while a senolytic relieved part of the damage without restoring NAD+
Ordinary mice have almost no dietary need for vitamin B3 because their bodies synthesize NAD+ from the amino acid tryptophan too efficiently. For decades the link between NAD+ decline and aging therefore remained circumstantial: the two processes run in parallel, but no one could switch the deficiency itself on and off. By engineering around this limitation, researchers created a mouse that, like a human, depends on dietary niacin. By controlling nothing but the diet, they switched whole-body NAD+ deficiency on and off for the first time and discovered two distinct sources of harm.
NAD+ is a coenzyme without which cells cannot generate energy, repair DNA, or activate the right genes; its decline has long been linked to aging and disease, and NAD+ precursors such as NR and NMN are sold as anti-aging supplements. In 2018 a laboratory at the University of Utah solved the problem of ordinary mice: they inserted a human enzyme that diverts NAD+ synthesis away from the tryptophan pathway, cutting off that backup route, and created the ANDY mouse line. The line's creators were joined by the gerontology group at the Kogod Center, Mayo Clinic, the same team that had earlier identified CD38 as the principal NAD+ consumer during aging. Together they carried out the first systematic investigation of what NAD+ deficiency does to an entire organism and whether the damage can be reversed; the results were published on 23 September in Nature Communications.
By removing niacin from the feed, the researchers produced the first controllable and reversible NAD+ deficiency in a mammal. These mice lost up to 55% of grip strength by the fourth week, developed kyphosis, lost bone and muscle mass, developed cataracts and greying fur, became frail, and died earlier: in a separate cohort of females kept on the deficient diet for 20 weeks, 40% died compared with zero in the control group. The muscle tissue itself looked nearly normal under the microscope: the loss of strength and mass was driven by activation of genes that promote muscle breakdown, while the tissue structure remained largely intact.
At the same time, cellular senescence rose across the tissues: cells that had stopped dividing but did not die accumulated and secreted inflammatory signals. Some mice received navitoclax, a drug that selectively kills such cells. It reduced their numbers and alleviated some symptoms (the mice became stronger and less frail) but did not raise NAD+ levels. This revealed two distinct sources of harm: the direct shortage of the coenzyme, and the accumulated senescent cells. Each can be targeted independently.
Restoring vitamin B3 to the diet largely returned the mice to normal: the frailty index dropped, endurance and bone recovered, and in the kidneys only 35 of 2922 altered genes remained abnormal, although tissue NAD+ did not fully recover. The transcriptome of NAD+-deficient mice overlapped only partially with that of naturally aged mice, and their epigenetic age did not accelerate at all despite severe coenzyme depletion. The authors themselves therefore describe ANDY as a model of NAD+ deficiency, not as a model of aging.
Alex Zhavoronkov, founder of the AI company Insilico Medicine, called the gap between functional recovery and NAD+ level recovery the most interesting finding in the paper:
This suggests that the senescent state, once established, has its own stability independent of the trigger that caused it.