Photograph by Stephanie Noritz
It has been the stuff of myth and fairy tale since the earliest times and across all cultures: an elixir of life that can make the old young again. But two drugs—already in use to treat blood cancer—are the first medications that can reverse some of the effects of aging, perhaps allowing people to remain healthy longer into old age.
It is the aging of our cells that causes us to develop most diseases, says Dr. Nir Barzilai, professor of medicine and genetics at the Albert Einstein College of Medicine in New York. “We know this, paradoxically, because of the amazing success we have had in treating heart disease. We have been able to save people from heart attacks with stents and bypass surgery—only to find that within a year or two they develop Alzheimer’s, diabetes or cancer at an alarming rate. Why? Because we have never treated the underlying aging of their cells. We have simply treated the disease manifestation.” So, explains Barzilai, if we can find the processes in the body that control aging and find a way to treat them, we will be able to protect people from the diseases of aging.
Barzilai heads a unique longevity study of more than 500 people who have reached the age of 100. The LonGenity study is looking at the genetic makeup of centenarians to identify the biological markers that explain why they live so long and so well. Because the remarkable thing about these people is not simply that they live to the age of 100, it is that they live to 100 in pretty good health. Just why they live that long without getting sick and dying is what Barzilai wanted to find out.
His first discovery was that it wasn’t because they did what the doctor ordered. “These people were more obese, smoked more and did less exercise than everyone else, so it certainly wasn’t their lifestyle,” said Barzilai in an interview at the American Society of Hematology conference last December in Florida, where he presented his latest research. Clearly, the centenarians’ genetic makeup was protecting them from what he calls the “environmental effects” of lifestyle. “If you are one of the one in 10,000 people destined to live to 100, you will be protected against environmental effects right from the outset.”
This finding led Barzilai to spend the last decade in the search for genes associated with exceptional longevity. He discovered that many of his centenarians have very high levels of good cholesterol, protecting them against heart disease, diabetes and Alzheimer’s. The reason their good cholesterol levels were so much higher than the average population was, he found, because of a fortunate gene mutation that makes the cholesterol ester transfer protein (CETP) gene less active.
Barzilai and his team have now also identified other mechanisms of aging that centenarians experience, but without getting ill. The most recent finding is that one of the ways that aging damages cells, leading to cancers and other degenerative illnesses, is through methylation, a natural process occurring in millions of sites throughout the body. Methylation is a process by which cells are reprogrammed over and over again in the course of our lifetimes. But as this repeated reprogramming occurs, certain components get out of whack, and genes malfunction or mutate, leading to disease.
“We know that methylation is a key biological process in aging because when we measure methylation levels we see huge differences between 65-year-olds and 95-year-olds,” said Barzilai. But, he added, there is so far no reliable way of knowing whether the problem is too much or too little methylation at any given site. “While centenarians have distinct changes in thousands of methylation sites compared with people who are 30 years younger, the impact of these changes on the biology is yet to be determined,” said Barzilai. “There is not one mechanism that applies throughout. It is going to be tissue specific, and it will take years of testing organ tissue to discover the danger points in each one because they are all different.”
The good news, he said, is that once that’s accomplished, “We will be able to reverse damage to cells that we have acquired through our environment.” In other words, people who aren’t genetically programmed to be centenarians may stay healthy for longer.
This is where we get lucky. Because quite by chance, there is already one tissue, blood, where researchers have had success in controlling methylation. In a serendipitous discovery, researchers working on a treatment for a rare form of blood cancer formulated a drug that restores faulty genes to normal. The drug azacitidine, or Vidaza, was developed to treat a group of cancers called myelodysplastic syndromes, or MDS. The drug works by normalizing the methylation levels in affected cells. It’s the first drug to work by utilizing “epigenetics,” or changes to our DNA caused by environmental factors including aging, stress, environmental radiation or toxins and other elements over which people have little control. In clinical trials, Vidaza doubled survival time in patients with the most severe form of MDS. Because Vidaza restores normal gene function to cancer-causing genes, it may well be able to prevent other cancers from forming, too.
Another blood cancer drug, lenalidomide, which clinical trials have shown can prolong the lives of multiple myeloma patients, also seems to have an application for the broader public. Lenalidomide works by increasing levels of positive cytokines—immune system chemicals that fight infections and fend off tumours. A recent trial on patients over 65, published in the journal Clinical Oncology in January, showed that minimal doses of the drug boosted patients’ levels of the important protective cytokine, interleukin-2, by more than a hundredfold, bringing their capacity to fight off disease to that of 30- and 40-year-olds. Larger-scale clinical trials are scheduled for this year to test the feasibility of lenalidomide as a daily immune-boosting pill for the elderly.
Also entering clinical trials this year is a drug that replicates the high “good” cholesterol patterns of Barzilai’s centenarians. The drug mimics the good genes of the centenarians by turning off the CETP gene. It has already shown that it can increase patients’ good cholesterol by 140 per cent and is now set to be tested on 30,000 patients. “The CETP inhibitor drug works for the rest of us exactly how the centenarians have it naturally,” said Barzilai.
While it is too soon for anyone to claim to have found the “fountain of youth,” these drugs are showing that they can turn the clock back in cells, with the prospect of helping the vast majority of us—who lack the natural genetic defences of centenarians—to remain far healthier longer into our old age.
