Life-sustaining NAD+ depletes with age but can now be replenished to maintain DNA repair capacity and cell vitality.

Nicotinamide adenine dinucleotide (NAD+) is a vital molecule inhabiting all living cells. NAD+ is essential in regulating energy metabolism and provides the substrate necessary to fuel enzymes that modulate key processes like DNA repair and cell survival. However, due to increased consumption and reduced synthesis, cellular NAD+ levels gradually decline with age. This loss of NAD+ leads to inefficient energy production that promotes mitochondrial dysfunction. Furthermore, without sufficient NAD+, cells become less resilient to stress and damage, leading to senescence (biological obsolescence). The consequences of senescence and mitochondrial dysfunction culminate in organ dysfunction, ultimately manifesting in age-related conditions. 

NAD+ Fuels Sirtuins

Sirtuins are a family of enzymes that modulate protective processes essential for cell survival, including DNA repair. These survival enzymes consume NAD+ to fuel their activity, so when cellular NAD+ levels drop, sirtuin activity diminishes. Thus, the decline in NAD+ that occurs with aging is intricately linked to reduced sirtuin activity. Increasing sirtuin activity has been shown to ameliorate age-related health conditions and extend the lifespan of multiple organisms, from yeast to mice. 

Sirtuins Use NAD+ to Modulate Proteins. Sirtuin enzymes break NAD+ down to nicotinamide to remove a molecular tag called an acetyl group (red) from proteins. Removing this tag modulates the activity of the protein, with each type of protein initiating a specific process, usually involving the promotion of cell survival.

When NAD+ levels and sirtuin activity are inadequate, macromolecules can no longer be metabolized efficiently, and less ATP is produced. Without sufficient levels of ATP, our cells cannot function optimally, and eventually, apoptosis (programmed cell death) is triggered. Because our organs and tissues are made up of cells, gradual increases in apoptosis coincide with progressive tissue and organ deterioration. Over time, this deterioration leads to functional decline. For example, when apoptosis is triggered in brain cells due to low ATP levels, brain tissue begins to deteriorate, and brain function declines. This decline in brain function is what we would call cognitive decline.