Increasing NAD+ to Improve Mitochondrial Function Slows Age-Related Hearing Loss in Mice

There is a great deal of hype surrounding the use of compounds that increase NAD+ levels in mitochondria, thereby improving the function of old tissue. This doesn't address the underlying molecular damage that leads to reduced NAD+ levels in later life, and thus might be thought of as something akin to pressing the accelerator harder in a car with a worn engine, but there is a slow accumulation of evidence for some degree of benefit to result. For example, reduced blood pressure in older hypertensive individuals, suggesting improved function of smooth muscle tissue in blood vessel walls. The example today is quite different, as the focus is on the function of cochlear tissue of the inner ear that is vital to hearing, and which suffers the loss of cells and cell function with age.

Age-related hearing loss (ARHL) or presbycusis is the most common cause of hearing loss and sensory disability, characterized by gradual deterioration of auditory sensitivity at all frequencies, with increasing age. ARHL still remains largely untreated. Despite the fact that the mechanism of ARHL has remained elusive, multiple studies have demonstrated that age-dependent oxidative stress, reactive oxygen species (ROS) metabolism, up-regulation of inflammatory responses, and mitochondrial dysfunction in parallel with cellular signaling and gene expression changes are implicated in this process. Particularly, structural changes and degeneration of inner ear cells, such as sensory hair cells, spiral ganglion neurons, and stria vascularis, are characteristics of aged mammals.

NAD+ and NADH are crucial mediators of energy metabolism and cellular homeostasis, as they act as cofactors for NAD+-dependent enzymes, including sirtuins (SIRTs), histones, and poly (ADP-ribose) polymerases (PARPs). Notably, cytosolic-free NAD+ levels decrease under various pathological conditions, including aging. There is strong evidence to support a role for SIRT1 in the process of aging and cell death, through deacetylation of targets such as NF-κB and p53. In addition, it has been proven that SIRT3 plays key roles in mitochondrial functions through deacetylation of mitochondrial proteins. Therefore, we hypothesize that long-term induction of high cellular NAD+ levels may produce protective effects against ARHL.

We investigated the effect of β-lapachone (β-lap), a known plant-derived metabolite that modulates cellular NAD+, on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD+ by β-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.



I'm sold on increasing NAD in the meantime. Questions: Do we clear out senescent cell first due to NAD studies showing extra inflammation if too many senescent cells exist.? Will 3 2 day rounds of 2400 mg total of fisetin every 3 months in an average 60 year old create enough sc clearance to provide benefit from NAD upregulation rather than inflammation? If so, do we go with NR supplements, NAD patches, or what was used in this study - B-lap?

Posted by: August at August 6th, 2019 7:02 PM

At this point, as I understand it, I would rather say that NAD+ deficiency and senecent cell buildup are largely orthogonal and independent pathways. So senolitics and NAD supplements child combined. Or used in succession.

Posted by: Cuberat at August 6th, 2019 9:35 PM

Biology is filled with the chicken or egg, what comes first, question. I don't think we know whether the analogy that increasing NAD+ levels later in life is like accelerating a worn engine is accurate.

Posted by: NY2LA at August 7th, 2019 2:54 PM
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