Researcher explores link of people's AGE levels to risks for cancer and other diseases
Researcher David Turner has a mission. He wants AGE, or advanced glycation end product, to be part of everyone’s vocabulary.
Knowing what the reactive metabolites are and the secrets to reducing their impact on the body can literally add years to people’s lives if they are willing to make some simple lifestyle changes, he said. A person’s AGE level is linked with diseases associated with chronic illnesses, including diabetes, cardiovascular disease and Alzheimer’s, and the evidence points to its link to cancer as well.
“Now, because of the Western diet, we’re consuming so many more of these AGEs than we ever did from outside sources. We’re giving ourselves all these fast foods and processed foods. All the unhealthy foods taste good because they have these AGEs in them. AGEs taste fantastic. It’s true – they are like flavonoids. All the charred areas on your grill, they are jam-packed with these advanced glycation end products.”
So how does he hope to change minds?
Turner regularly talks to community groups, charming them with his British accent and his gift of relaying science news in bite-sized morsels. Though his popularity drops a bit when he shares the soaring AGE levels in bacon and other popular food items, most people understand how compelling the research is. It’s one reason why funding is growing in this area.
Of the $7 million grant MUSC recently received from the National Institutes of Health and the National Cancer Institute, about $2 million will be directed to AGE-related research. Marvella Ford, the principal investigator, specializes in population health and health disparities. The grant, which will develop a South Carolina Cancer Disparities Research Center, is a partnership between South Carolina State University and the MUSC Hollings Cancer Center.
In this grant, Turner is being tapped for his expertise in AGEs. One area of focus is an intervention study with 60 prostate cancer survivors, looking at how diet and exercise might affect AGE levels.
Turner will be collaborating with researcher Mahtabuddin Ahmed at South Carolina State University. Ford said the higher the AGE levels, it is thought the poorer the prostate cancer prognosis and outcome.
Turner’s work shows there is big difference in AGE levels between blacks and whites, she said. “Blacks actually have higher levels of AGEs even before cancer diagnosis. They’re linked with poorer prognoses and worse outcomes in prostate cancer. The idea is if we can drive down the level of AGEs, we can make more equitable health outcomes for blacks and whites, and it may help reduce disparity in prostate cancer survival rates.”
It’s not just prostate cancer, either, as the interest in the link between all cancers and AGE levels is growing. Researchers in Turner’s lab have found that some chemotherapy drugs, such as tamoxifen, stopped working when breast cancer cells were treated with AGE . “If you treat cells with tamoxifen and add AGEs, the tamoxifen actually doesn’t work anymore – at all. This has implications that if you have a high-AGE diet, that could be affecting your cancer treatment,” Turner said.
Animal models suggest high-AGE diets may be promoting cancer growth and making recurrence more likely, he said. The goal is to find out how AGEs affect humans.
As part of figuring that out, Turner is working with colleagues on two clinical trials exploring the role of AGEs in breast and prostate cancers. The breast cancer trial, led by Carolyn Britten, M.D., is seeing whether AGE levels can be reduced in women with metastatic breast cancer if they take compounds thought to reduce AGEs.
In the pilot trial, women receiving endocrine therapy for metastatic estrogen receptor negative breast cancer will take metformin and oligomeric proanthocyanidin complex (OPC) for 12 weeks. Turner said the trial will determine if the medication regimen will lower AGE levels and how this might affect treatment outcomes. It also will see if high AGE levels are associated with increases in body mass index or insulin resistance, which also can predict poor outcomes for breast cancer patients.
The prostate clinical trial, led by researcher Michael Lilly, M.D., is a continuation from a pilot trial with 13 patients that found AGE levels came down in nine patients when they took the antioxidant OPC. “It’s been known for a while that these AGE and reactive oxygen species are very much intertwined. There’s a feedback loop. If you have high AGEs, that produces reactive oxygen species and if you have high reactive oxygen species, that produces AGEs. That’s one of the things that leads to chronic inflammation.”
Turner said the new trial is exploring if certain drugs, metformin and OPC, have an effect on the AGE levels in the blood in prostate cancer patients and whether those levels have an effect on cancer.
“This is the first time AGEs have been looked at in clinical trials in cancer. That’s a real push forward. AGEs have been related to cardiovascular disease, diabetes, Alzheimer’s and Parkinson’s, but when it comes to cancer, there’s very little out there. We have found this niche that is there,” he said.
“AGEs can promote the growth of cancer cells and alter the signaling pathways within the tumor itself, which basically makes it grow quicker. That is what we’ve shown in the lab, so it’s good to see this connection between the lab and the clinic.”
Turner said enough is known about the negative impact of AGE levels for it to be a wake-up call for the public.
AGEs come from two sources. They are produced in the body naturally as sugar is broken down for energy. Diet is the other factor. Consuming foods high in sugar, fat or that are highly processed substantially increases the levels. What also matters is how the foods are prepared. Dietary AGEs are naturally present in raw animal-derived foods, but cooking techniques that involve high heat, such as grilling and frying, also increase the amount.
In a prostate cancer animal model, mice fed a high-AGE diet had their tumors grow three- to four- fold quicker. “We were shocked,” he said about the results. “The same experiment in high-fat diets does increase tumor growth but nowhere near what the high-AGE diet does.”
The other key message is that AGE levels in the body seem to have more of an impact at critical points of development, creating windows of susceptibility. For example, mice fed high-AGE diets during puberty later showed abnormal growths in mammary development that could be a precursor to cancer.
“The breasts develop as we grow older versus other organs that develop in utero. That makes them susceptible to environmental influences during different windows of development, such as puberty. It’s not until later in life that this can develop into cancer. It’s called metabolic memory. These things that happen during puberty imprint the cells in the body, and then later in life, given other triggers such as a gene mutation, it can promote cancer.”
Turner especially wants parents to know about the research because very simple changes they make in their kids’ diets can significantly impact their future health.
Some general tips and a tip sheet (pdf) that can be downloaded:
In the GOAL or Getting on Board to and Active Lifestyle study, researchers Ford, Turner and Gayenell Magwood, Ph.D., RN, put 10 breast cancer patients through a cardiovascular rehab program at MUSC and looked at AGE levels at the beginning and end of the program. “We’re seeing the AGEs coming down because of this program,” Turner said. “In most of the patients, they came down four- to fivefold and that was just doing this for 12 weeks. If AGEs are thought to promote cancer growth, it is thought if you can keep them low, especially in breast cancer survivors, you might reduce the chances of them having a relapse. You’re reducing an inflammatory environment in the body that is conducive for cancer growth.”
Turner recommends increasing physical activity, while making dietary changes.
“It’s not cheap to eat healthy, and a lot of families can’t do that. But some of my tips they can do quite easily,” he said. “This builds up over a lifetime. If you can change your children’s diets two or three times a week to have less AGEs, imagine how much less that would be over a lifetime.”
One of the goals of Turner and his MUSC colleagues is to promote the link between tumor biology and lifestyle. “I’m trying to bring that link to the forefront of research.”
Some renowned researchers, such as Yusuf Hannun, think that up to 80 percent of cancers are preventable based on lifestyle change. “It’s a mixture of lifestyle and genes. I want to link lifestyle and the biological mechanisms of tumors together,” Turner said. “Then we can treat cancers more efficiently and prevent them from occurring in the first place.”
He’s excited to be collaborating with Ford on the new grant, as it will add to the existing research that sheds light on how to lower health disparities. The increase in research funding also gets him a step closer to making AGE a household word.
“I didn’t know what they were four years ago, and the biological effects are huge. In the general public, not many people have heard of them yet, but they are fundamental to so many chronic diseases. Mice fed a low-AGE diet live a third longer. These should be on food labels.”