Aging comes with an accumulation of damage and dysfunction in cells, among which researchers single out disrupted NAD+ metabolism and a growing number of senescent cells. These two processes are closely linked: senescent cells secrete inflammatory factors and can deplete NAD+ in tissues. Earlier studies showed that NAMPT expression rises in aging cells, but how this affects NAD+ metabolism remained unclear. The work sits off on its own: there is almost no one nearby, and the closest neighbors deal with plasma in herb extraction, peptide design and brain memory. Here the scale is different. It is not individual molecules or phenomena but systemic regulation of aging through a metabolic hub.
The experiments used human IMR90 fibroblasts, which were driven into senescence by irradiation, the HRAS oncogene or chemotherapy drugs. To assess NAD+ metabolism, the researchers used isotopic labeling: cells were fed nicotinamide with deuterium, and its conversion into NAD+ and back was tracked. NAMPT was activated with the compound SBI-0802162, a derivative of SBI-797812. In C57BL/6J mice of different ages (3, 18 and 20 months), the team assessed NAD+ levels in tissues, transcriptomic changes, senescence markers and functional measures (frailty index, rotarod). The combination of the activator with nicotinamide was added to the chow for up to 12 weeks.
In senescent cells, NAMPT levels are elevated, but the rate of NAD+ synthesis and consumption is reduced. This creates a "dormant" enzymatic reserve. The activator SBI-0802162 increased NAD+ in senescent cells 2.7-fold (versus 1.9-fold in proliferating cells), disrupted mitochondrial respiration and selectively reduced the viability of aging cells without affecting normal ones. In mice, the activator depleted nicotinamide in the blood, so it was combined with dietary nicotinamide. This combination raised NAD+ in muscle and heart, suppressed age-related inflammatory and interferon programs (especially in liver and muscle), and lowered levels of the senescence marker p16Ink4a. In old mice, the combination slowed the progression of frailty and preserved motor function on the rotarod, while also reducing body weight and food intake with no signs of toxicity.
The work shows for the first time that senescent cells possess an excess but unused pool of NAMPT, which can be activated to selectively eliminate these cells. Unlike neighboring studies that examine individual molecules or phenomena, this one proposes a systemic strategy combining metabolic and cellular therapy for aging. The combination of an NAMPT activator with nicotinamide overcomes the substrate limitation and produces a more consistent effect across tissues than either agent alone.
The topic could move toward clarifying the exact mechanism by which senescent cells die when NAMPT is activated: whether mitochondrial dysfunction is the cause or the consequence, and which type of cell death is involved. Researchers will also need to study how the combination affects appetite and body weight, and to determine optimal doses for long-term use. It may be possible to develop more specific NAMPT activators with less influence on feeding behavior.
The results could influence gerontology, the development of senolytics and the treatment of age-related diseases linked to inflammation and metabolic disorders.
Long-term studies in mice with separate groups for each agent are needed, along with measurements of NAD+ flux and secondary nicotinamide metabolites, as well as assessments of body composition and energy metabolism.
The work addresses the fundamental problem of senescent cell heterogeneity and their metabolic dependence. The discovery of a "dormant" NAMPT enzymatic reserve raises the question of which other metabolic hubs might be vulnerable in aging cells. It also remains unresolved why NAMPT accumulates but does not work, and how this relates to NAD+ feedback.
Senescent cells, despite their "old age," contain more of the enzyme NAMPT than young ones, but use it less efficiently, like a library with a huge collection and a closed reading room.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.