Sirtuins and NAD+ in Aging / Longevity Control
Source: Nature Magazine
The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.
It’s so long ago
Since the first discovery of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity of the silent information regulator 2 (Sir2) family (‘sirtuins’),1 the field of sirtuin biology has been evolving rapidly over the past 16 years. Many researchers from different fields have encountered sirtuins in their own research, enriching our knowledge of this fascinating family of enzymes. It is now clear that sirtuins are involved in the regulation of many fundamental biological processes throughout the body.2,3 Furthermore, it has been revealed that sirtuins possess much broader enzymatic activities, namely, deacylases, including deacetylase, desuccinylase, demaloynylase, deglutarylase, long-chain deacylase, lipoamidase, and ADP-ribosyltransferase.4,5 All these enzymatic activities specifically require NAD+, and the catalytic mechanism of this NAD+ dependency has been studied extensively.6 Clearly, sirtuins have evolved to respond to the availability of NAD+, an essential currency of cellular metabolism and DNA damage repair, and convert this information to many different biological outputs. In this particular review article, we will focus on this intimate connection between sirtuin function, aging/longevity control in particular, and their indispensable co-substrate, NAD+.
The origin of the connection between NAD+ and sirtuins is ancient. For instance, vibriophage KVP40 possesses a minimal set of genes for NAD+ biosynthesis and consumption, namely, the genes encoding two key NAD+ biosynthetic enzymes, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT),2,3 and a sirtuin family protein (Figure 1).7 Although why such a minimalistic organism keeps these three genes in its genome remains unclear, one potential explanation is that controlling the host cell’s metabolism and proliferation in a NAD+-dependent manner could provide benefits for this particular vibriophage to efficiently produce progeny in the host cell. Such a NAD+/sirtuin-mediated virus–host relationship might be a prototype for the much more complex inter-tissue communication mediated by NAMPT and the mammalian sirtuin SIRT1.8 As discussed later in this review, NAMPT and SIRT1 comprise multiple layers of feedback regulatory loops inside cells and between tissues and organs, and contribute to the systemic regulation of mammalian aging and longevity.9,