Published OnlineFirst May 8, 2014; DOI: 10.1158/2159-8290.CD-ND2014-009
NEWS IN DEPTH
Q&A: Brian Kennedy on Aging and Cancer A better understanding of the mechanisms that underlie aging might reduce the burden of disease Damage to DNA, such as that caused by oxidative stress, leads to cancer and possibly to aging. Yet there may be a trade-off between cancer and aging: The tumor-suppressing proteins RB1 and p53 can cause cells to senesce, limiting the proliferation of damaged cells that might cause cancer. However, the accumulation of senescent cells, which express p16INK4a and ARF, contributes to age-related pathology. Brian Kennedy, PhD, president and CEO of the Buck Institute for Research on Aging in Novato, CA, recently spoke with Cancer Discovery’s Suzanne Rose about the questions researchers are trying to answer to tease apart the complex relationship between senescence, aging, and cancer. What spurred researchers to study senescence? Researchers noticed that if you let cells divide in cell culture, they stopped after a while and became senescent. People thought this would cause aging, but when they started looking for senescent cells in aging mice and humans, they couldn’t find many. In the meantime, researchers realized that cells have to avoid senescence to promote cancer formation—in other words, cellular senescence is a protective mechanism that inhibits tumor formation. Now we know that senescent cells put out inflammatory signals that interfere with other cells in the environment, and that may cause a tissue to become dysfunctional with age. This has reinvigorated the theory that senescent cells promote aging. It may also be that inflammatory cytokines secreted by senescent cells have a tumor-promoting role. The senescent response in the pretumorigenic cell is good because it inhibits the tumor, but the senescent secretory profi le of that cell might make cells around it more likely to become inflamed, promoting both cancer and aging. We’re trying to understand this. Can you eliminate senescent cells or halt their proinflammatory signals? If so, will that inhibit or slow the formation of cancer? These are interesting questions, but we don’t know the answers. You can generate mice using transgenics that have ablated senescent cells, and there are studies going on to try to figure out whether they live longer, develop fewer cancers, or become resistant to other diseases of aging. The main study so far has been in a progeria model. Researchers found that although the animals did not live longer, many of the pathologies of progeria were reduced. That was an exciting finding. People are also looking for drugs that can kill senescent cells or inhibit their secretory response, but we don’t yet know what would happen in a normal mouse if you got rid of the senescent cells. Why do cells senesce? Why don’t they die? Cells can go down one of two different pathways as they age: an apoptotic pathway or a senescent pathway. It’s still not totally
clear why cells choose one pathway or the other. It might be that there’s more continuity to the tissue if the cells become senescent and still exist, but we don’t know. Does chemotherapy contribute to aging? Evidence is starting to accumulate to support that. Children who had extensive chemotherapy and were “We’ve always said that aging causes disease, but now we’re starting to cured of cancer who have wonder to what extent disease been followed for 20 or 30 causes aging,” says Brian Kennedy. years have some biologic properties of much older individuals. One way to interpret that is that chemotherapy obviously doesn’t just target the cancer cells; it may be causing significant DNA damage to a tissue or multiple tissues, depending on how it’s administered, and that may promote elements of aging. Chemotherapy also kills a lot of cells. Adult stem cells need to repopulate the damaged tissue, and rounds of chemotherapy may be reducing their capacity to continue to work over time. We’ve always said that aging causes disease, but now we’re starting to wonder to what extent disease causes aging. There may be a complex interplay between the two. For example, when you get a chronic viral infection like cytomegalovirus, it activates stress response pathways. It may be that some events that we call disease and thought we’d cured are accelerating aging. This is an emerging area of research. What challenges is the field facing? We can give drugs that slow down aging—some of which are clinically approved for use in humans—to mice, and they live longer, they’re healthy longer, they’re resistant to cancer. We’ve also identified lots of genetic mutations that extend the lifespan. The challenge is that we don’t know why. We need to have a better understanding of the basic mechanisms that are causing aging and how they are linked to the drugs’ activity. The other thing is that we need to move more into translation, but it’s hard to think about how to do that because, unlike cancer, aging is not considered a disease. It’s not clear how you would measure it. Are there biomarkers for aging? Can we develop drugs that reduce those biomarkers? A third challenge is that mouse models are not extremely predictive of the human condition. I think one reason is that most cancers are age related, but the studies we do are in young mice. The drug response between a young and old individual is very different. One of the things we can do to make the mouse a better model for most human cancers is to try to find ways to induce the tumor in older mice and then do the drug testing. If it’s an age-related disease, it’s a good idea to incorporate aging into your model. Some people are doing that, but not many, because it’s more expensive and takes longer. ■
JUNE 2014CANCER DISCOVERY | 627
Downloaded from cancerdiscovery.aacrjournals.org on June 8, 2015. © 2014 American Association for Cancer Research.
Published OnlineFirst May 8, 2014; DOI: 10.1158/2159-8290.CD-ND2014-009
Q&A: Brian Kennedy on Aging and Cancer Cancer Discovery 2014;4:627. Published OnlineFirst May 8, 2014.
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NEWS IN DEPTH
Q&A: Brian Kennedy on Aging and Cancer A better understanding of the mechanisms that underlie aging might reduce the burden of disease Damage to DNA, such as that caused by oxidative stress, leads to cancer and possibly to aging. Yet there may be a trade-off between cancer and aging: The tumor-suppressing proteins RB1 and p53 can cause cells to senesce, limiting the proliferation of damaged cells that might cause cancer. However, the accumulation of senescent cells, which express p16INK4a and ARF, contributes to age-related pathology. Brian Kennedy, PhD, president and CEO of the Buck Institute for Research on Aging in Novato, CA, recently spoke with Cancer Discovery’s Suzanne Rose about the questions researchers are trying to answer to tease apart the complex relationship between senescence, aging, and cancer. What spurred researchers to study senescence? Researchers noticed that if you let cells divide in cell culture, they stopped after a while and became senescent. People thought this would cause aging, but when they started looking for senescent cells in aging mice and humans, they couldn’t find many. In the meantime, researchers realized that cells have to avoid senescence to promote cancer formation—in other words, cellular senescence is a protective mechanism that inhibits tumor formation. Now we know that senescent cells put out inflammatory signals that interfere with other cells in the environment, and that may cause a tissue to become dysfunctional with age. This has reinvigorated the theory that senescent cells promote aging. It may also be that inflammatory cytokines secreted by senescent cells have a tumor-promoting role. The senescent response in the pretumorigenic cell is good because it inhibits the tumor, but the senescent secretory profi le of that cell might make cells around it more likely to become inflamed, promoting both cancer and aging. We’re trying to understand this. Can you eliminate senescent cells or halt their proinflammatory signals? If so, will that inhibit or slow the formation of cancer? These are interesting questions, but we don’t know the answers. You can generate mice using transgenics that have ablated senescent cells, and there are studies going on to try to figure out whether they live longer, develop fewer cancers, or become resistant to other diseases of aging. The main study so far has been in a progeria model. Researchers found that although the animals did not live longer, many of the pathologies of progeria were reduced. That was an exciting finding. People are also looking for drugs that can kill senescent cells or inhibit their secretory response, but we don’t yet know what would happen in a normal mouse if you got rid of the senescent cells. Why do cells senesce? Why don’t they die? Cells can go down one of two different pathways as they age: an apoptotic pathway or a senescent pathway. It’s still not totally
clear why cells choose one pathway or the other. It might be that there’s more continuity to the tissue if the cells become senescent and still exist, but we don’t know. Does chemotherapy contribute to aging? Evidence is starting to accumulate to support that. Children who had extensive chemotherapy and were “We’ve always said that aging causes disease, but now we’re starting to cured of cancer who have wonder to what extent disease been followed for 20 or 30 causes aging,” says Brian Kennedy. years have some biologic properties of much older individuals. One way to interpret that is that chemotherapy obviously doesn’t just target the cancer cells; it may be causing significant DNA damage to a tissue or multiple tissues, depending on how it’s administered, and that may promote elements of aging. Chemotherapy also kills a lot of cells. Adult stem cells need to repopulate the damaged tissue, and rounds of chemotherapy may be reducing their capacity to continue to work over time. We’ve always said that aging causes disease, but now we’re starting to wonder to what extent disease causes aging. There may be a complex interplay between the two. For example, when you get a chronic viral infection like cytomegalovirus, it activates stress response pathways. It may be that some events that we call disease and thought we’d cured are accelerating aging. This is an emerging area of research. What challenges is the field facing? We can give drugs that slow down aging—some of which are clinically approved for use in humans—to mice, and they live longer, they’re healthy longer, they’re resistant to cancer. We’ve also identified lots of genetic mutations that extend the lifespan. The challenge is that we don’t know why. We need to have a better understanding of the basic mechanisms that are causing aging and how they are linked to the drugs’ activity. The other thing is that we need to move more into translation, but it’s hard to think about how to do that because, unlike cancer, aging is not considered a disease. It’s not clear how you would measure it. Are there biomarkers for aging? Can we develop drugs that reduce those biomarkers? A third challenge is that mouse models are not extremely predictive of the human condition. I think one reason is that most cancers are age related, but the studies we do are in young mice. The drug response between a young and old individual is very different. One of the things we can do to make the mouse a better model for most human cancers is to try to find ways to induce the tumor in older mice and then do the drug testing. If it’s an age-related disease, it’s a good idea to incorporate aging into your model. Some people are doing that, but not many, because it’s more expensive and takes longer. ■
JUNE 2014CANCER DISCOVERY | 627
Downloaded from cancerdiscovery.aacrjournals.org on June 8, 2015. © 2014 American Association for Cancer Research.
Published OnlineFirst May 8, 2014; DOI: 10.1158/2159-8290.CD-ND2014-009
Q&A: Brian Kennedy on Aging and Cancer Cancer Discovery 2014;4:627. Published OnlineFirst May 8, 2014.
Updated version
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Access the most recent version of this article at: doi:10.1158/2159-8290.CD-ND2014-009
Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
Downloaded from cancerdiscovery.aacrjournals.org on June 8, 2015. © 2014 American Association for Cancer Research.
