Does a retrograde response in human aging and longevity exist?

The retrograde response (RR) is a compensatory mechanism by which mutant st rains of yeast are able to cope with mitochondrial DNA (mtDNA) impairments by up-regulating the expression of the stress-responder nuclear genes and s ignificantly increasing lifespan. Starting from the observation that both m tDNA variability and Tyrosine hydroxylase (THO, stress-responder gene) vari ability are correlated with human longevity, we asked ourselves whether mec hanisms similar to RR may exist in humans. As a first investigative step we have analyzed the distribution of the: mtDNA inherited variants (haplogrou ps) according to THO genotypes in three sample groups of increasing ages (2 0-49 years; 50-80 years; centenarians). We found that the mtDNA haplogroups and the THO genotypes are associated randomly in the first group, while in the second group, and particularly in the centenarians, a non-random assoc iation is observed between the mtDNA and nuclear DNA variability. Moreover, in centenarians the U haplogroup is over-represented (p = 0.017) in subjec ts carrying the THO genotype unfavorable to longevity. On the: whole these findings are in line with the hypothesis that longevity requires particular interactions between mtDNA and nuclear DNA and do not exclude the possibil ity that an RR has been maintained throughout evolution and it is present i n higher organisms. (C) 2000 Elsevier Science Inc. All rights reserved.