A Push and a Pull for PARP-1 in Aging

DUAL NATURE: After mild DNA damage by a variety of environmental insults PARP-1 activates the repair machinery, but after severe damage PARP-1 becomes highly activated and contributes to nuclear cell-death signaling by depleting NAD+ and ATP. It may also cause apoptosis-inducing factor (AIF) to translocate to the nucleus. Free PolyADP-ribose (PAR) and associated molecules may elicit other pro-apoptotic effects. Understanding the mechanisms that underlie aging remains a bedeviling problem, but not because of a lack of answers. If anything, there seem to be too many answers – or at least enticing clues – each leading in different directions. Thus, researchers are bound to get excited when a single molecule appears to play roles in several perceived longevity pathways, raising hopes that one could weave a coherent theory. Several strands of evidence have linked PolyADP-ribose polymerase-1 (PARP-1) to potential aging-associated processes such as DNA-repair, telomere maintenance, and apoptosis. But many still question PARP's role in longevity. Studying ways to upregulate PARP-1 is "a major component of my current research," says Alexander Bürkle, biology department chairman at the University of Konstanz, Germany, and one of the protein's more ardent champions. Bürkle and colleagues found in the 1990s that more efficient PARP-1 function was associated with longevity in 14 mammalian species,1 including human centenarians.2 Later research suggested that the protein cooperates with two others mutated in premature-aging disorders.34 Bürkle is now examining the effects of transfecting PARP-1 expression vectors into cell cultures. DAMAGE CONTROL Some researchers don't agree that PARP-1 is positively associated with longevity. Drug companies are studying PARP inhibitors because research suggests they attenuate some serious conditions – most of them associated with aging (see sidebar).5 This effect is thought to stem from the fact that PARP overactivation can kill cells. Thus "direct experiments are not supporting the story" about PARP and longevity, says Csaba Szabó, research professor at Semmelweis University Medical School in Budapest, Hungary. Bürkle says the apparent contradictions are reconcilable through a better understanding of the protein and its evolutionary role. PARP-1 is a prominent member of a family of PARP proteins, several of which are implicated in similar functions.6 Their DNA-repair role emerged in the 1980s. Although PARP's role was sometimes described as more supporting than central, it positioned PARPs as potential players in longevity, given a longstanding theory that accumulating DNA damage and/or declining DNA-repair capabilities contribute significantly to aging. When Bürkle's group linked PARP-1 to mammalian longevity, it seemed to fit this picture neatly. A DEVASTATING SYNDROME Courtesy of George M. Martin © 1996 Lippincott & Wilkins The effects of Werner syndrome, a premature-aging disorder linked indirectly to the PARP protein family, on a Japanese-American woman. As a teenager, she looked normal, but at 48 the ravages of Werner were apparent. Out of several disorders classified as premature-aging syndromes, Werner syndrome is considered the one whose effects most closely resemble typical aging. Yet as with those other conditions, it doesn't precisely mirror normal aging. Nonetheless, researchers believe such disorders may provide valuable information. The protein mutated in Werner syndrome interacts directly with PARP-1, a protein linked to longevity in mammals. (From Medicine 45:177–221, 1996) The nature of PARP's DNA-repair activities was less clear, however. Researchers saw that PARPs add branched chains of ADP-ribosyl units onto various nuclear proteins, most often histones and themselves. But how ribosylation acts in DNA repair or other processes isn't quite understood. Nevertheless, outlines of a proposed mechanism are emerging in terms of a PARP-effected chromatin loosening that lets other repair factors reach damaged sites.7 In 2003, researchers at the National Institutes of Health reported a strong interaction between PARP-1 and the protein mutated in Werner syndrome, a premature-aging disorder. Others found that PARP-1's DNA-repair functions depend on the protein mutated in another such disorder, Cockayne syndrome.3 Later work expanded on these findings and "further supports the connection between PARP activity and aging," said Lucio Comai, associate professor of molecular microbiology and immunology at the University of Southern California, Los Angeles. PARP-1 and several other family members also have been found to facilitate telomere maintenance,6 through mechanisms not fully understood. This provides another aging link, some say; a widely studied hypothesis holds that a gradual lifelong shortening of telomeres contributes to aging. But muddling the picture, no single PARP alone is crucial for telomere maintenance, says Prakash Hande, assistant professor in the department of cancer biology at the National University of Singapore. Moreover, whatever PARP-1 does for telomeres, it's part of just one of at least "two or three pathways" of telomere maintenance. The DNA-repair role of PARPs rings a similar theme: They're implicated in only one or two of several known repair pathways, and PARP-1-knockout cells seem healthy when free of other DNA-damaging stressors or protein knockouts. A YIN AND A YANG PARP Inhibition A new class of drugs in clinical trials could clarify fundamental questions about PolyADP-ribose polymerase (PARP), researchers say. They're "a burgeoning field," says Andrew Salzman, president and CEO of Inotek Pharmaceuticals, Beverly, Mass., which is conducting Phase II clinical trials on PARP inhibitors for heart attack. New York City-based Pfizer Inc. has completed Phase I trials for them in melanoma, and several other companies are studying them preclinically. Salzman, a clinician, says "almost everybody" has raised an obvious concern: Suppressing DNA repair might be bad. But no experiments suggest even long-term PARP inhibition does harm, he says. "Nor has the FDA ever expressed any concerns" – especially considering many of the diseases involved can be swift killers, and the intended treatment short-term. Conditions including reperfusion injury, inflammation, and heart attack provoke spikes in PARP activity that deplete its raw material, NAD+. This spurs apoptosis or, in worse cases, necrosis, potentially tissue-wide. The inhibitors would hinder this, and are also thought to act against cancer.1 Their prolonged use would raise worries of not only DNA damage, but also suppression of the constant microscopic inflammations required for immune defense, says Alexander Bürkle, chairman of the biology department at the University of Konstanz in Germany. But "if it's a question of life or death, then I would be clearly willing" to use them. Most of the diseases at issue are indeed that way, Salzman says. He also notes new findings that PARP inhibition destroys certain breast tumors,2 the first time DNA repair "has been exploited therapeutically to kill a cancer." "Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors," Jagtap P, Szabó C, Nat Rev Drug Discov , 2005 Vol 4, 421-40"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase," Bryant HE, Nature , 2004 Vol 434, 913-7 Nevertheless, researchers have been identifying new possible roles of PARP in genome upkeep. "I think PARP really is a key player" in DNA repair, says Vilhelm Bohr, chairman of the molecular gerontology department at NIH's National Institute on Aging. "That would explain the findings with PARP and aging." Moreover, PARP's forte seems to be fixing oxidative DNA lesions, a particular type of DNA damage that has even stronger links to aging. None of this yet suggests clear conclusions about aging or prevention, Bohr adds, but it shows why further study is important. Bürkle says PARP-enhancing compounds might deserve more scrutiny. For instance, he says, studies have already found the Parkinson drug L-selegiline extends animal life spans, possibly via PARP potentiation. The findings are mixed, Bürkle acknowledges; but he opines that this is largely because researchers haven't bothered replicating each other's methods. "One must carefully read the Materials and Methods" in these studies, he says. "If you do this sort of meta-analysis, it's hard to deny there is some effect." Szabó and others don't buy the supposed PARP-longevity link. "You can find all sorts of associations, [but] if something plays a role you have to show it directly," he says. Caenorhabditis elegans could serve as a simple test, he adds. "If it played an important role in aging, you would expect that if you put worms in soil with a lot of PARP inhibitors you would see a big change [in aging processes]. Nobody has shown that." Comai doesn't dismiss a PARP-longevity link but he, too, sees pitfalls. Studies have shown a "yin and yang effect" of PARP, he says. "On the one hand, it promotes cell survival; on the other hand, overactivating it might favor cell death." Indeed, severe DNA damage triggers massive PARP activation quickly consuming NAD+, the raw material for PARP activity. This directs the cell to apoptosis, or in more extreme cases, necrosis.5 In some conditions, such as heart attack, such processes spread mayhem widely enough to threaten whole organisms. Something else that could dampen hopes of harnessing PARP against aging is that PARP may compete strongly for NAD+ supplies with Sir2, another longevity-linked enzyme,8 says Zie Zhang, principal scientist at Guilford Pharmaceuticals in Baltimore. This raises the specter of a trade-off between two longevity elixirs, he adds – another yin-and-yang trap that leaves him "not quite convinced" that more PARP activity is good. Bürkle calls this reasoning intriguing, but speculative, as Zhang readily admits. Bürkle devotes more attention to the other, better-documented trade-off involving PARP – that between genome repair and cell death. This could leave people perplexed about what to do with PARP, he acknowledges. But a solution could ultimately be to pursue therapies that enhance PARP activity throughout most of life, then depress it when specific conditions call for it. "The two strategies can be reconciled," he insists, in light of a widely held theory on the evolutionary basis of aging – antagonistic pleiotropy – which says natural selection promotes genes that enhance health early in life, at the expense of later well-being. After all, he notes, "once you have generated your offspring," evolution cares little "if you drop dead."

A Push and a Pull for PARP-1 in Aging

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Jack Lucentini

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August 2005

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