Here's the proximate physical implication of the ratio (from the Wikipedia article on NADH).

The balance between the oxidized and reduced forms of nicotinamide adenine dinucleotide is called the NAD+/NADH ratio. This ratio is an important component of what is called the redox state of a cell, a measurement that reflects both the metabolic activities and the health of cells. The effects of the NAD+/NADH ratio are complex, controlling the activity of several key enzymes, including glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase. In healthy mammalian tissues, estimates of the ratio between free NAD+ and NADH in the cytoplasm typically lie around 700; the ratio is thus favourable for oxidative reactions. The ratio of total NAD+/NADH is much lower, with estimates ranging from 0.05 to 4. In contrast, the NADP+/NADPH ratio is normally about 0.005, so NADPH is the dominant form of this coenzyme. These different ratios are key to the different metabolic roles of NADH and NADPH.

So here's my question: how does this manifest in vertebrate aging? Is it something that's simply the resultant of other aging processes, or can the ratio also contribute to aging in a certain way?

  • 1
    $\begingroup$ What's the source of this quote? $\endgroup$
    – kmm
    Jan 25 '12 at 23:34
  • $\begingroup$ Wikipedia (have added a note for clarification). $\endgroup$ Jan 26 '12 at 3:38

This study found a statistically significant decline in NAD+:NADH ratios and in intracellular NAD+ with age in the organs of rats.

They discuss that the activation of PARP - the NAD-dependent enzyme Poly(ADP-ribose) polymerase-1 instrumental in DNA repair - increases in aging organs (heart, liver, kidneys). This depletes cellular NAD+ levels via poly(ADP-ribosylation) of proteins. This reduced cellular NAD+ then reduces the effectiveness of Sirtuins (Sirt1) which can deacetylate tumor-suppressor proteins such as p53.

Here's schematic showing the basic idea from their figure 10:

enter image description here

So, the inference is that oxidative stress in vertebrates increases with age due to lowered cellular NAD+ - i.e., consistent with the free-radical theory of aging. This could mean that lowered cellular NAD+, NAD+/NADH in any given individual may well decrease said individuals lifespan.

The authors of the first study (Braidy et al 2011) suggest that therapies involved in maintaining high NAD+ levels may alleviate age-associated disorders.


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