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Age-related NAD⁺ decline.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite that is reported to decline in concentration in tissues of aged animals. Strategies to increase NAD⁺ availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD⁺ metabolism remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD⁺, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD⁺ and changes in the composition of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD⁺ content of specific cells and subcellular compartments as well as determining the threshold levels at which NAD⁺ depletion triggers physiological consequences in different tissues. Understanding how NAD⁺ metabolism changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clinical trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD⁺ availability can impact human physiology. Thus, it is an exciting time for NAD⁺ research, with much remaining to be learned in terms of both basic biology and potential therapeutic applications.

SUBMITTER: McReynolds MR

PROVIDER: S-EPMC7442590 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

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Age-related NAD⁺ decline.

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