For example, long-term dietary restriction can prevent the onset of common age-related hearing loss in C57BL/6 mice. Independent manipulation of these signaling molecules can recapitulate, or abrogate, some of the broader biological effects of environmental changes such as fasting or dietary restriction.

Such signaling metabolites include acetyl-CoA (coenzyme A), another carrier of high-energy bonds that is also substrate for a widely prevalent protein posttranslational modification (lysine acetylation), and S-adenosyl-methionine, which similarly is substrate for a common posttranslational modification of histones and other proteins (methylation) ( 43). NAD +, a simple energy carrier, thereby acts as a fulcrum around which many cellular processes can be regulated in response to changes in the external environment. During times of fasting, or relative scarcity of cellular energy, more NAD is in the oxidized state, and sirtuins and PARP can be more active. Sirtuins and PARP thereby regulate cellular functions ranging from gene expression and DNA damage repair to fatty acid metabolism ( 134). However, in its oxidized form (NAD +), NAD is also a cofactor for sirtuin enzymes and poly-ADP-ribose polymerase (PARP), both of which consume NAD in the course of removing acyl groups from and adding poly-ADP to proteins, respectively. Nicotinamide adenine dinucleotide (NAD), for example, accepts high-energy electrons from reactions in the catabolism of glucose and fatty acids and transfers them to acceptor molecules to either produce ATP or perform energetically demanding metabolic reactions. Cellular energy metabolites act as key mediators of many of these pathways, linking the external environment to changes in cellular function ( 43). It is increasingly understood that the effects of fasting involve the actions of specific molecular signaling pathways. Fasting and dietary restriction, for example, have long been the most consistently effective intervention to slow various effects of aging and prolong the life span of otherwise healthy mammals. Many of these nutrient-responsive pathways have broader effects on health and are emerging as regulators of fundamental mechanisms of aging. Mammals have developed a variety of mechanisms for adapting to changes in the environment, particularly changes in food availability and nutrient stress.

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