A NAMPT activator combined with nicotinamide slowed the progression of frailty in old mice

A NAMPT activator combined with nicotinamide slowed the progression of frailty in old mice

In an August 7 preprint, a team from Sanford Burnham Prebys described SBI-0802162, a compound that activates the NAMPT enzyme. In cultured human cells, it increased NAD+ levels more strongly in senescent cells than in dividing cells, and prolonged exposure reduced the viability of senescent cells. After 12 weeks of treatment with the compound and nicotinamide, the frailty index of 18-month-old mice remained stable. In the rotarod test, the authors observed a strong trend toward better performance than in the control group.

Senescent cells stop dividing after damage or stress. The authors looked for a vulnerability in their NAD+ metabolism. NAD+ is a molecule involved in energy production, DNA repair, and cellular responses to stress. When NAD+ is consumed, nicotinamide remains. The NAMPT enzyme initiates its conversion back into NAD+.

Isotope labeling allowed the researchers to distinguish the total NAD+ pool from the rates of its synthesis and consumption. In cultured human connective tissue cells driven into senescence by irradiation, NAMPT was abundant, although NAD+ synthesis and consumption were slower. This finding suggested that some NAMPT activity might remain unused.

SBI-0802162 activates NAMPT. Within one day, NAD+ levels increased 2.7-fold in fibroblasts with radiation-induced senescence and 1.9-fold in normal dividing cells. Prolonged exposure to SBI-0802162 altered mitochondrial respiration and gene activity in senescent cells. In a separate experiment, it reduced the viability of senescent cells, while the viability of dividing cells remained unchanged.

In mice, SBI-0802162 reduced blood nicotinamide levels, so the researchers added it to the animals' food. The combination with SBI-0802162 increased NAD+ levels in tissues and produced different changes in sets of active genes associated with inflammation and senescence. The authors found the most consistent changes in skeletal muscle. During the 12-week experiment, the frailty index increased in old control mice but remained unchanged in mice receiving the combination. Weight loss during the first three weeks, averaging 14%, had a substantial effect on this index. In the rotarod test, the authors observed a strong trend toward better performance than in the control group.

In mice, SBI-0802162 reduced blood nicotinamide levels, so the researchers added nicotinamide to the animals' food. The combination of SBI-0802162 and nicotinamide increased NAD+ levels in tissues and produced different changes in the activity of genes associated with inflammation and senescence. The authors found the most consistent changes in skeletal muscle. During the 12-week experiment, the frailty index increased in old control mice but remained stable in mice receiving the combination. Weight loss during the first three weeks, averaging 14%, had a substantial effect on this index. In the rotarod test, the authors observed a strong trend toward better performance than in the control group.

Senolytics selectively reduce the viability of senescent cells. Here, the authors propose using NAD+ metabolism to identify such compounds. They suggest that abundant NAMPT, combined with slower NAD+ synthesis and consumption, leaves a reserve of unused enzyme activity. The activator combined with nicotinamide sharply increases NAD+ levels. The authors demonstrated selective loss of viability in cell cultures. In mice, they measured NAD+ levels, the activity of genes associated with inflammation and senescence, and physical function.