Improving Lifespan and Healthspan in a Disorder Causing Early Aging

Improving Lifespan and Healthspan in a Disorder Causing Early Aging

A team of researchers lead by Drs. Evandro Fang and Vilhelm Bohr of the National Institute of Aging–National Institutes of Health have identified a possible intervention for use in the treatment of ataxia telangiectasia (A-T). A-T is a genetic neurodegenerative disorder caused by a mutation in the ATM gene, which is key in repairing damage to DNA. Patients experience difficulty with movement and coordination, a weakened immune system, and, ultimately, premature death. Typically, the first symptoms are seen in pre-school-age children, but unfortunately, A-T is not properly diagnosed until some years later because children do not develop at the same rate or in the same manner. The average age of death for A-T patients is 25.

The molecular basis of the cerebellar atrophy and neurodegeneration seen in A-T patients is not fully understood. Mitochondrial damage and NAD+ depletion are key features of the disorder. Therefore, Fang et al. investigated three different methods to boost NAD+: the use of an SIRT1 activator, a PARP inhibitor, and NAD+ precursors. By replenishing NAD+, lifespan was extended and healthspan improved in the ATM-deficient animal models; the severity of A-T was diminished, neuromuscular function was normalized, and memory loss was delayed.

While it remains to be seen whether NAD+ supplementation will translate to the clinical treatment of A-T patients, the findings in this particular study suggest innovative therapeutic approaches to battle this disease and possibly other aging disorders that are due to deficiencies in DNA repair. In addition to suggesting therapeutic interventions, the work in this study also links two aging theories, DNA damage accumulation and mitochondrial dysfunction, that explain A-T symptoms.

To get access to the full paper in Cell Metabolism, click here.

Preserving DNA Methylation During Aging

Preserving DNA Methylation During Aging

One of the negative aspects of aging is the decreased ability to maintain normal cellular functions, which eventually manifests as disease. Optimal maintenance of DNA methylation is critical for normal cellular functions, but, as organisms age, the number of methyl groups on DNA drops. This may result in the development of disorders such as cancer, impaired glucose/lipid metabolism, and cardiovascular diseases.

The two major dietary sources of methyl groups in animals are methionine and choline. Past research has shown that rats and mice fed diets low in methionine (MR) but optimal in choline are less susceptible to aging-associated diseases and outlive mice on regular diets. In this study, Senior Scientist Dr. Sailendra Nichenametla and his team hypothesized that an MR diet induces changes in DNA methylation, which ultimately contributes to its beneficial effects. Dr. Nichenametla investigated this hypothesis in mice of two different ages (young and adult) by feeding each either a control diet (normal levels of choline and methionine; CF) or an MR diet (normal choline levels, but 80% less methionine).

Findings from this study suggest that an MR diet, despite containing comparatively fewer methyl groups, prevents loss of DNA methylation in the liver. While seeming paradoxical, these findings are plausible and highlight the complexity of biological systems. A decrease in a number of methyl groups coming from methionine may not have an effect because of the presence of choline, which also contributes to methyl groups. However, the MR diet results in lower levels of S-adenosylhomocysteine (SAH). Previous studies found that SAH levels increase during aging.

Here at OFAS, we strive to provide insight into the mechanistic basis of lifespan extension by MR diet through our research. Based on our findings, we conclude that an MR diet improves the efficiency of DNA methylation maintenance systems in adult mice, but has no effect in young mice, likely due to the fact that young animals already have lower levels of SAH compared to adult mice. With this study, we are one step closer to finding ways to slow down the process of aging-associated diseases such as cancer.

Access the full paper here.