Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span.

Abstract

Poly(ADP-ribosyl)ation is a eukaryotic posttranslational modification of proteins that is strongly induced by the presence of DNA strand breaks and plays a role in DNA repair and the recovery of cells from DNA damage. We compared poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) activities in Percoll gradient-purifled, permeabilized mononuclear leukocytes from mammalian species of dfferent maximal life span. Saturating concentrations of a double-stranded octameric oligonucleotide were applied to provide a direct and maximal stimulation of PARP. Our results on 132 individuals from 13 different species yield a strong positive correlation between PARP activity and life span (r = 0.84; P << 0.001), with human cells displaying -5 times the activity of rat cells.Intraspecies comparisons with both rat and human cells from donors ofall age groups revealed some decline ofPARP activity with advancing age, but it was only weakly correlated. No sigicant polymer degradation was detectable under our assay conditions, ruling out any interference by poly(ADPribose) glycohydrolase activity. By Western blot analysis of mononuclear leukocytes from 11 species, using a crave antiserum directed against the extremely well-conserved NADbinding domain, no correlation between the amount of PARP protein and the species' life spans was found, suggesting a greater specific enzyme activity in longer-lived species. We propose that a higher poly(ADP-ribosyl)ation cacit in cells from long-lived species might contribute to the efficient maintenance of genome integrity and stability over their longer life span.Interestingly, Pero et al. (20) We therefore set up a method to provide a direct stimulus for PARP in permeabilized cells-i.e., addition of saturating amounts of a double-stranded oligonucleotide (29 (3,4). DNA break binding leads to an immediate and drastic activation of the catalytic center located in the carboxyl-terminal NADbinding domain; the latter is separated from the DNA-binding domain by a central automodification domain. A large number of studies done in a variety of experimental systems led to the view that poly(ADP-ribosyl)ation plays a role in DNA repair (5) and other cellular responses to DNA damage, such as cell cycle perturbations (6), DNA amplification (7)(8)(9), and malignant transformation (10, 11). Apart from this, poly-(ADP-ribosyl)ation was thought to play a role in DNA replication (12, 13), integration of transfected foreign DNA into the cell genome (14, 15), intrachromosomal homologous recombination (16), differentiation (17, 18), and aging (19-22). In no case, however, have the molecular mechanisms been elucidated so far. MATERIALS AND METHODS

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

“…Another concept critical to the interpretation of the data in this study is that relationships between BER (or other DNA repair activities) and lifespan may be highly cell-type specific. Previously, various authors have described positive correlations between species' MLSP and poly(ADP-ribose) polymerase activity (Grube and Bürkle 1992), NER (Cortopassi and Wang 1996), double-strand break recognition (Lorenzini et al 2009), and telomere length maintenance (Haussmann et al 2003) in fibroblasts and blood cells. These cell types will have very different characteristics than those Table 1) and NP=no nuclear protein extract.…”

Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

“…31 The DNA repair capacity of the normal population between the ages of 20 and 60 years declines at a rate of 0.61% per annum. 32 The relationship between PARP activity, aging and longevity has been studied; 33 and it has been shown that maximal oligonucleotide-stimulated PARP activity in permeabilized peripheral blood mononuclear cells decreases slightly but significantly and linearly with the age of the donor up to 95 years; however, in an independent analysis of Epstein-Barr virus-immortalized lymphoblastoid cell lines from centenarians (i.e., individuals who have avoided the pathologic and often lethal conditions typically associated with aging, such as cancer) and controls aged 20 -70, an association was found between high poly(ADP-ribosyl)ation capacity and longevity. 34 Our present results are compatible with the latter findings and may indicate that protection against cancer (exemplified by laryngeal cancer) is one mechanism by which PARP activity contributes to longevity.…”

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

“…Consistent with this view is the finding that individuals with a polymorphism that confers reduced PARP activity have increased risk of cancer (see below). In addition, despite a general decline in PARP activity with age (Grube and Bürkle, 1992;Chevanne et al, 2007) that may correspond to the increase in cancer incidence with age (http://info.cancerresearchuk.org/cancerstats/mortality/age/), lymphocytes from people who live to a very old age (4100 years) without developing cancer have higher PARP activity (Muiras et al, 1998). With regard to the association of PARP-1 polymorphisms with activity and cancer, the T2444C single-nucleotide polymorphism (SNP; Cottet et al, 2000) results in an amino-acid substitution, Val762Ala, in the PARP-1 activity domain.…”