Werner Syndrome is Strongly Mediated by Mitochondrial Dysfunction

Researchers here report that NAD+ upregulation to improve mitochondrial function, via supplementation with nicotinamide riboside and nicotinamide mononucleotide, does a decent job of rescuing the life span of flies and worms with the genetic mutation that causes Werner syndrome. It is not quite all the way restored to match wild-type animals, but close. Werner syndrome is a DNA repair deficiency condition in which patients exhibit, at the high level, what appears to be accelerated aging: early onset of a range of age-related conditions, early mortality. It is not, however, accelerated aging. Natural aging stems from rising levels of molecular and cellular damage, but damage of a particular blend of varieties. Werner syndrome is one specific class of damage, stochastic nuclear DNA damage, elevated to a very large degree. There are important differences, and it is never all that clear as to whether we can apply lessons learned in DNA deficiency conditions to normal aging - it depends greatly on the fine details in each case.

The most interesting point here is that, in at least short-lived species such as flies and worms, the harm done by this particular DNA repair deficiency is to a large degree mediated by an early collapse in mitochondrial function. It remains to be see whether this is also true in mammals: the literature might lead us to expect that high levels of stochastic mutational damage to nuclear DNA could be causing all sorts of other harms. Mitochondria are the power plants of the cell, responsible for packaging the chemical energy store molecule ATP needed to power cellular operations. NAD+ is vital to mitochondrial operation, and its levels decline with age, alongside mitochondrial function. Artificially boosting NAD+ levels has been shown to restore the ability of mitochondria to function in a more youthful fashion, but as yet there is only the one small clinical trial to show health benefits in older humans.

Can we take this paper as evidence for mitochondrial decline to be very important in normal aging? That would be the question. If I were speculatively joining pieces of the jigsaw puzzle, I would take this study, and put it next to the recent finding that suggests double strand breaks in nuclear DNA will cause epigenetic drift of the sort observed in aging. So the more of this sort of DNA damage, more epigentic change. Problems with mitochondria are perhaps proximately caused by changing levels of specific proteins, such as those necessary for the process of fission. Too little fission results in ever larger mitochondria that are not easily cleared out by the maintenance processes of mitophagy when they become worn and damaged. Protein levels are, of course, under epigenetic control. Perhaps this all fits together, but it still needs a lot of work to shore up the relevant evidence; it should be treated as speculative.

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

We report that Werner syndrome (WS) is associated with a significant mitochondrial dysfunction, mainly manifested as defective mitophagy. This is reflected in lower NAD+ levels across species from worms to humans. NAD+ supplementation improves mitochondrial function and other age-related metabolic outcomes. Mitochondrial disease can manifest itself in multiple clinical outcomes amongst which neurodegeneration and impaired metabolism are common. Some features of WS may be explained by genomic instability due to mutation in the gene encoding the Werner protein (WRN), an important DNA helicase/exonuclease involved in DNA repair, telomere and heterochromatin maintenance, and cancer regulation. However, the relationship between WRN mutations and the syndrome's severe dysregulation of energy metabolism is unclear.

Mitochondrial quality and function decline with age, contributing to insulin resistance and metabolic diseases in the elderly. Mitochondrial quality control is regulated by biogenesis and mitophagy. Mitophagy involves the targeting of damaged mitochondria to the lysosomes wherein the mitochondrial constituents are degraded and recycled. Defective mitophagy is prominent in aging and age-predisposed disorders, including metabolic diseases and neurodegeneration. However, the role of mitophagy in WS has not been investigated.

The metabolic molecule nicotinamide adenine dinucleotide (NAD+) is emerging as a fundamental regulator of mitochondrial homeostasis, genome stability, neuroprotection, healthy aging, and longevity. Interestingly, genetic and/or pharmacological upregulation of intracellular NAD+ levels protects against obesity and type 2 diabetes in rodents, and against age-related diseases and neurodegenerative diseases such as Alzheimer's disease.

We therefore examined whether mitochondrial dysfunction and NAD+ depletion occur in WS, and if so, how it contributes to the molecular pathology in WS. We report that NAD+ depletion is a major driver of the severe metabolic dysfunction in WS through dysregulation of mitochondrial homeostasis. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.