Since Ponce de Leon, people have searched for a fountain of youth, something that provides a longer life with fewer of the afflictions of aging. Might it exist in a still-unknown substance? And can modern scientists find it?
Calorie restriction in laboratory animals leads to a longer life span. But very few people would consider a consistent calorie restricted diet to provide a high quality of life. Now, for the first time, there’s a substance (rapamycin) that’s been proven to lengthen the life span of mice, in part through work done at the Laboratory. It’s not a magic elixir—indeed, it dangerously suppresses the immune system—but it will give clues into how and why we age. And, perhaps, ways we could alter the process to our benefit.
Analysis: Female sexual maturity in mammals and an evolutionary theory of aging
By Kevin Flurkey, Ph.D.
Scientists including Jackson Professor David Harrison have found a number of genes that appear to control lifespan in mice. In 2009 the National Aging Institute’s Intervention Testing Program, which includes the Harrison lab, demonstrated the first pharmaceutical intervention to extend the lifespan of a mammal by more than 10% when they administered rapamycin to mice late in life. But even that important discovery has not yet led to interventions that can be applied to humans.
All the mutations we know of that increase lifespan in mice have been found through reverse genetic strategies: by testing a known mutant gene for effects on aging and lifespan, or by structurally altering a gene and then testing the effects of the induced mutation. While such studies have demonstrated that lifespan can be increased in mammals through genetic means, presumably by retarding aging, they appear to do so at a physiological “cost”—i.e., none of these mutant mice could survive in the wild because some important physiological function is typically compromised by the mutation.
In fact, there is almost no natural genetic variation in the “lifespan” genes we have found through analysis of mutants, probably because of the physiological cost of diminishing the function of these genes. Thus, any attempt to medically mimic, for humans, the lifespan-enhancing effect of these mutations would also produce an impairment that would probably shorten the lifespan of anyone who doesn’t live in a bubble (or at least in sterile, pathogen-free mouse colony with constant temperature and no stress).
Rong’s approach was to look for genetic variants that already exist in nature. It seems unlikely that the lifespan-enhancing effect of a natural genetic variant would cost too much—otherwise it would have been removed from the gene pool. Thus, genes that produce normal variations in lifespan probably provide much better targets for biomedical interventions.
Rong was not the first to think of this—scientists have been trying to map lifespan loci using natural variation for decades—but the loci that have been found seem to be as evanescent as the Cheshire cat’s smile. This is no surprise: Lifespan is a horrible phenotype to try to map. There’s relatively low heritability, and unidentified environmental variation has such a large influence on lifespan variance that it can mask the genetic influence.
Rong’s innovation was to use evolutionary theory to refine his focus. The evolutionary theory of aging actually predicts that the genes that regulate aging will be found among the genes that regulate development and maturation. In fact George Williams, one of the two people who developed the evolutionary theory of aging in the 1950s, actually stated that if you could halt maturation, you would stop aging. (Dave Harrison calls this the Peter Pan corollary, after the boy who refused to grow up, and so never grew old, although it hasn’t worked so well for me.)
The key here is that the genes that regulate natural variation in maturational rate should be much easier to find than genes that regulate aging. For example, when looking at “maturational” genes, there’s no confusion from disease genes that affect lifespan (like cancer genes) but have no little relation to inherent aging rates. In fact, Rong showed that, in mice, the heritability of the marker he used (age of vaginal patency) is five to 10 times greater than the heritability of lifespan, which greatly improves the chances of finding these genes.
To my knowledge, Rong is the first scientist to apply evolutionary theory to guide the search for the actual genes that regulate aging in mammals. Success depends on finding, among the genes that regulate the maturational phenotype, genes that also regulate lifespan. This PNAS paper reports the first evidence of the success of this strategy, and Rong has identified a few very promising candidate genes.
Kevin Flurkey is an associate research scientist in the laboratory of Jackson Laboratory Professor David Harrison, Ph.D.
Larry Closson feels blessed. He's 85 years old—"my father and grandfather didn't make it past their 70s"—lives with his son and family, and enjoys his time out of the house.
"I look forward to coming here every day so much. I like to read, but otherwise, when you get older, you can get terribly bored without a place like this."
"Here" is the Straus Center in Southwest Harbor, Maine, which provides day programs for seniors like Larry. Each day Larry and his friends gather for music, games, a mid-day meal and other activities. The center has a casual feel, friendly and welcoming, that makes it easy to forget the activities and facilities are carefully planned.
"Larry is in the early stages of dementia," says Debra Chalmers, director of adult day services at the center, a community resource for seniors with memory problems and their caregivers. "His long-term memory is intact, but his short-term memory is limited."
"I'm sorry to say that he has not been assessed to ascertain a specific diagnosis, which is a common occurrence for many older adults who display symptoms that fall under the umbrella of "dementia." I look forward to future research helping unlock some of the mysteries around dementia and other brain diseases," Debra says.
Larry's long-term memory is formidable indeed. To reminisce with him is to revisit a Downeast Maine that no longer exists. Born in Sullivan in June 1925, he grew up on an island estate in a house without telephone or electricity.
"My father took care of the estate and served as boat captain and chauffeur for the owners, who were grandchildren of Longfellow. I loved it. It was very quiet, very peaceful, not like around here nowadays with all the hustle and bustle in the summer."
Larry did profit from the summer tourist business as a teenager, keeping lobster traps and selling what he caught. He used the money he earned to buy clothing for the school year. Asked if he ever kept any of his catch, Larry shudders. "Oh, no, never. I hate eating lobsters myself."
World events swept him away from the quiet for what turned into 20 years. He enlisted in the Navy and served in the South Pacific during World War II and the Korean War, flying off aircraft carriers and returning to the deck with what he vividly remembers as a "controlled crash landing."
"I've seen so many things happen, so much history, but you don't think about it like that when you're going through it. And when it's war, it's just awful, terrible experiences."
Larry retired from the military in 1962 and quickly returned to his Maine roots. He raised five children, all of whom still live in the area. His military-honed mechanical expertise contributed to both his civilian work and hobbies.
"I loved to work on old cars and used to restore Model A Fords. I can't do that any more—my leg sometimes goes out on me like a broken airplane landing gear." He laughs. "Sometimes I feel like an old car—I've got too many replacement parts in me!"
Kevin Flurkey, Ph.D., is among the researchers at The Jackson Laboratory leading the effort to find ways to extend our health span, the years of robust health and high quality of life.
“We’re looking for the processes that control aging," Flurkey says. "The ultimate goal is to delay the onset of age-related diseases and increasing health span."
With advances such as the drug rapamycin, Flurkey wants to find out not only why we age, but how to use that knowledge.
As for Larry, his future is now, and he lives it with gusto.
"The folks here at the center, they're perfect, absolutely wonderful. I have no complaints. I'm very lucky and I know it."
The Search magazine"Live long, live well"
Harry Lodge, M.D.