Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity?

Abstract

Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master "longevity regulatory gene" that translates a variety of environmental stresses into lifespan extension by activating the sirtuin family of longevity deacetylases. Master longevity genes such as PNC1 are highly adaptive because they allow organisms to respond in a concerted way to adversity and to rapidly evolve life strategies to compensate for a changing environment. Hence, they should be well conserved. We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging.

Fig. 1

The sirtuin/class III HDAC deacetylation reaction and regulation by nicotinamide. Step 1 is a reversible base-exchange reaction in which a peptidyl intermediate is formed between the acetyl group on the lysine of the polypeptide to generate 1′-O-α-peptidylamidate-ADP-ribose, with the release of nicotinamide (NAM). Step two is the deacetylation of the lysine by hydrolytic attack. The peptidyl intermediate is sufficiently stable to permit regeneration of NAD⁺ in the presence of elevated nicotinamide concentrations. Figure adapted from Bitterman et al. (2002).

Fig. 2

Space-filling model of Sir2-Af2 and nicotinamide inhibition. Nicotinamide (NAM) in green is shown bound in the “C-pocket” of Sir2-Af2 adjacent to an NAD⁺ molecule in the active site. Inhibition by NAM is proposed to occur when free NAM binds in the C-pocket and reacts with the relatively long-lived peptidyl intermediate, driving the reaction in reverse to generate NAD⁺ and acetylated target protein (image provided courtesy of C. Wolberger, Johns Hopkins Medical School).

Fig. 3

The two known pathways for the salvage of NAD⁺ from nicotinamide. Mammals recycle NAD from nicotinamide (NAM) in two steps rather than four, bypassing the production of nicotinic acid (NA). Pnc1, NAM deamidase; Nampt, NAM phosphoribosyltransferase; Nmnat, nicotinamide mononucleotide adenylyltransferase.

Fig. 4

Nampt (PBEF/Visfatin) as a regulator of cell survival, metabolism and longevity. In this model, Nampt is upregulated by nutrient deprivation, caloric restriction (CR) and other forms of mild stress, and localizes with Nmnat to various organelles to catalyze NAM depletion and NAD⁺ production. This stimulates sirtuins, PARP and other NAD⁺ dependent enzymes that boost cell survival and alter metabolism to promote the survival of mammals during adversity. Nampt is also secreted from adipocytes as Visfatin and it bind to the insulin receptor to trigger glucose uptake by peripheral tissues. Prolonged upregulation of Nampt might mimic aspects of CR and extend mammalian lifespan, as PNC1 does in S. cerevisiae.