{"id":222862,"date":"2017-03-03T15:48:43","date_gmt":"2017-03-03T20:48:43","guid":{"rendered":"http:\/\/www.rochester.edu\/newscenter\/?p=222862"},"modified":"2017-03-24T14:39:47","modified_gmt":"2017-03-24T18:39:47","slug":"study-identifies-key-factor-in-dna-damage-associated-with-aging-222862","status":"publish","type":"post","link":"https:\/\/www.rochester.edu\/newscenter\/study-identifies-key-factor-in-dna-damage-associated-with-aging-222862\/","title":{"rendered":"Study identifies key factor in DNA damage associated with aging"},"content":{"rendered":"
\"David
David Goldfarb. (University photo \/ J. Adam Fenster)<\/figcaption><\/figure>\n

In a recent study, Rochester scientists made two important contributions to DNA damage research. First, though scientists could previously point to an association between DNA damage and aging, the Rochester group has demonstrated a causal relationship between reduced DNA damage and extended lifespan. Second, the researchers have identified a cellular factor\u2014an enzyme called topoisomerase 2, or Top2, implicated in DNA damage\u2014that can be targeted to reduce that damage. The findings are published in the journal Aging<\/em>.<\/a><\/strong><\/p>\n

\u201cThis part of the puzzle has been missing from the DNA damage theory of aging,\u201d says David Goldfarb<\/a><\/strong>, professor of biology. There are many examples of DNA damage being associated with aging, but never has a reduction in DNA damage been shown to extend lifespan. The study also shows how this information may have therapeutic potential.<\/p>\n

Goldfarb\u2019s lab exposed yeast\u2014which ages much like humans\u2014to a lifespan-shortening, drug-like molecule that acts on Top2 and helped the lab uncover Top2’s role.<\/p>\n

Top2 introduces double strand breaks into DNA as part of its catalytic cycle. The breaks must then be resealed. \u201cEvery once in a while Top2 gets trapped on the DNA before it can seal the breaks,\u201d Goldfarb says. \u201cWhen that happens, at least in young cells, there are a number of back-up systems that recognize the breaks and repair them.\u201d<\/p>\n

However, a number of researchers have shown that DNA damage repair systems decline as cells age, causing the unrepaired DNA breaks created by Top2 to persist. The unrepaired double strand breaks cause aging, diseases like cancer, and, ultimately, death.<\/p>\n

\u201cMany investigators are trying to reverse aging by boosting the backup DNA repair systems in aging cells,\u201d Goldfarb says. However, the new findings by his lab suggest that \u201ca simpler therapeutic approach may be to administer drugs that reduce the activity of enzymes like Top2 that cause DNA damage in the first place.\u201d<\/p>\n

In the paper, his lab shows how a three- to five-fold reduction in Top2 activity in aging yeast cells resulted in a 20 to 30 percent increase in lifespan.<\/p>\n

The lab would not have uncovered Top2\u2019s role if it had not first discovered LSI, an unusual Top2 poison. Unlike other Top2 poisons, which are usually highly toxic, LS1 shortens lifespan without affecting the health of young cells. When introduced into yeast cells, LS1 prevents Top2 from repairing its DNA double strand breaks. That\u2019s not a problem in young cells with healthy DNA repair systems, but deadly in older cells, Goldfarb says,<\/p>\n

However, by transiently stopping Top2 from repairing its own breaks, LS1 enhances the potency of anti-cancer drugs that themselves target Top2 in human cancer cells.
\n<\/strong><\/p>\n

For example, doxorubicin\u2014a chemotherapy drug used for breast cancer, leukemia, and other cancers\u2014causes cardiotoxicity when overused. \u201cYou can give patients only so much doxorubicin; there\u2019s a lifetime dosage limit,\u201d Goldfarb says. However, if the potency of doxorubicin were increased by also administering LS1, the same therapeutic affects might be achieved by using less of the drug\u2014reducing the chance of side effects\u2014and extending the utility of these frontline cancer drugs.<\/p>\n

Gregory Tombline, a PhD researcher at Rochester, and postdoc Jonathan Millen are primary contributors to the study. John Nitiss, an expert on Top2 at the University of Illinois at Chicago’s College of Pharmacy also contributed. The Drug Discovery Division at Southern Research Institute in Birmingham Alabama performed the high throughput lifespan screen that identified LS1. The project was funded by grants from the National Institutes of Health and a contract to the university from Calorics Pharmaceuticals.<\/p>\n","protected":false},"excerpt":{"rendered":"

There are many examples of DNA damage being associated with aging, but never has a reduction in DNA damage been shown to extend lifespan. Rochester research has made this connection, and identified an enzyme that can be targeted to reduce that damage. <\/p>\n","protected":false},"author":286,"featured_media":223162,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[116],"tags":[13942,18722,29502,18572,16072],"class_list":["post-222862","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-sci-tech","tag-aging","tag-department-of-biology","tag-featured-post-side","tag-research-finding","tag-school-of-arts-and-sciences"],"acf":[],"yoast_head":"\nStudy identifies key factor in DNA damage associated with aging<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.rochester.edu\/newscenter\/study-identifies-key-factor-in-dna-damage-associated-with-aging-222862\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Study identifies key factor in DNA damage associated with aging\" \/>\n<meta property=\"og:description\" content=\"There are many examples of DNA damage being associated with aging, but never has a reduction in DNA damage been shown to extend lifespan. 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