Neurodegeneration in accelerated aging.
The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic strategy for treating accelerated aging disorders and potentially age-associated neurological decline seen in the normal population.
mscheibye@sund.ku.dk.
Moren
M
Scheibye-Knudsen
D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D001816:Bloom Syndrome / Q000235:genetics; D003057:Cockayne Syndrome / Q000235:genetics / Q000503:physiopathology*; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology; D019871:Dyskeratosis Congenita / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D063306:Mitophagy; D009243:NAD / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011371:Progeria / Q000235:genetics / Q000378:metabolism; D011038:Rothmund-Thomson Syndrome / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism; D059506:Telomere Shortening; D014898:Werner Syndrome / Q000201:enzymology / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000235:genetics
D009243:NAD; D011065:Poly(ADP-ribose) Polymerases; C447939:SIRT1 protein, human; D056564:Sirtuin 1