cientists claim to be a step closer to reversing the ageing process after rejuvenating worn out organs in elderly mice. The experimental treatment developed by researchers at the Dana-Farber Cancer Institute, Harvard Medical School, turned weak and feeble old mice into healthy animals by regenerating their aged bodies. The surprise recovery of the animals has raised hopes among scientists that it may be possible to achieve a similar feat in humans – or at least to slow down the ageing process. An anti-ageing therapy could have a dramatic impact on public health by reducing the burden of age-related health problems, such as dementia, stroke and heart disease, and prolonging the quality of life for an increasingly aged population. “What we saw in these animals was not a slowing down or stabilisation of the ageing process. We saw a dramatic reversal – and that was unexpected,” said Ronald DePinho, who led the study, which was published in the journal Nature. “This could lead to strategies that enhance the regenerative potential of organs as individuals age and so increase their quality of life. Whether it serves to increase longevity is a question we are not yet in a position to answer.” The ageing process is poorly understood, but scientists know it is caused by many factors. Highly reactive particles called free radicals are made naturally in the body and cause damage to cells, while smoking, ultraviolet light and other environmental factors contribute to ageing. Nevertheless scientists have isolated a gene sequence that appears to determine how fast our bodies age, the first time a link between DNA and human lifespan has been found.
The research, published in February 2010 in the journal Nature Genetics, gives the kind of insight into the biology of ageing that has not emerged from work on other strategies that claim to extend lifespan, such as consuming vast quantities of antioxidants or pursuing a severely calorie-restricted diet. The research highlights the difference between chronological age and biological age, the latter of which is determined by our genetic makeup and lifestyle factors, such as diet and smoking. Two people of the same age can have biological ages that differ by more than 10 years. A team led by Professor Nilesh Samani and Professor Tim Spector at King’s College, London found a common sequence of DNA was strongly linked to a person’s biological age. In a study of nearly 3,000 people, around 38% inherited one copy of the gene variant and were biologically three to four years older than those who did not carry the sequence. A minority of 7% inherited two copies of the DNA sequence and were on average six to seven biological years older. The majority of the population, 55%, do not carry any copies of the variant. The study, published in the journal Nature Genetics, was prompted by the huge variability in the age at which people develop medical problems that are often considered diseases of the elderly. “I see patients in their 80s with high blood pressure who have healthy coronary arteries and I see people in their 40s who don’t seem to have any risk factors yet have advanced heart disease,” Samani said. “We think this kind of variability must have something to do with premature ageing.” Most of the cells in our bodies contain long molecules of DNA called chromosomes that have protective caps at either end called telomeres. Every time a cell divides, the telomeres shorten, like plastic tips fraying on a shoelace. When the telomeres become very short, the cell starts to malfunction and show signs of ageing. From blood samples, Samani and Spector found a particular gene sequence was more common in people who had unusually short telomeres for their age.
The section of DNA was found on chromosome three, next to a gene called TERC, which makes an enzyme that repairs telomeres when they shorten. People who carry one or two copies of the genetic sequence probably make less of the enzyme, called telomerase, when they are growing in the womb. This means they are born with shorter telomeres, and so are prone to ageing more quickly. “The effect may be built in at a very early stage in life. If you’re born with shorter telomeres, there’s evidence you will be prone to heart disease and other age-related diseases,” Samani said. For instance, research shows that people with longer telomeres in their blood cells have an increased number of healthy years beyond the age of 60, according to Ronald A. DePinho, the lead author of the telomerase mice study. Conversely, people over the age of 60 who have the shortest telomeres display higher rates of diabetes, cardiovascular disease and Alzheimer’s. The Harvard group focused on telomere shortening, breding genetically manipulated mice that lacked an enzyme called telomerase that stops telomeres getting shorter. Without the enzyme, the mice aged prematurely and suffered ailments, including a poor sense of smell, smaller brain size, infertility and damaged intestines and spleens. But when DePinho gave the mice injections to reactivate the enzyme, it repaired the damaged tissues and reversed the signs of ageing. “These were severely aged animals, but after a month of treatment they showed a substantial restoration, including the growth of new neurons in their brains,” said DePinho. But repeating the trick in humans will be more difficult. Scientists are unlikely to reverse the ageing process by boosting telomerase in people’s bodies.
Mice make telomerase throughout their lives; in humans the enzyme is almost completely deactivated after birth, but is switched back on in cancer cells so they can divide endlessly without dying. “Introducing telomerase might protect you from heart disease, but if you turn it on willy nilly you could cause cancer instead,” Samani said. Raising levels of telomerase in people might slow the ageing process, but it makes the risk of cancer soar. DePinho said the treatment might be safe in humans if it were given periodically and only to younger people who do not have tiny clumps of cancer cells already living, unnoticed, in their bodies. David Kipling, who studies ageing at Cardiff University, said: “The goal for human tissue ‘rejuvenation’ would be to remove senescent cells, or else compensate for the deleterious effects they have on tissues and organs. Although this is a fascinating study, it must be remembered that mice are not little men, particularly with regard to their telomeres, and it remains unclear whether a similar telomerase reactivation in adult humans would lead to the removal of senescent cells.” Lynne Cox, a biochemist at Oxford University, said the study was “extremely important” and “provides proof of principle that short-term treatment to restore telomerase in adults already showing age-related tissue degeneration can rejuvenate aged tissues and restore physiological function.” DePinho said none of Harvard’s mice developed cancer after the treatment. The team is now investigating whether it extends the lifespan of mice or enables them to live healthier lives into old age. Tom Kirkwood, director of the Institute for Ageing and Health at Newcastle University, said: “The key question is what might this mean for human therapies against age-related diseases? While there is some evidence that telomere erosion contributes to age-associated human pathology, it is surely not the only, or even dominant, cause, as it appears to be in mice engineered to lack telomerase. Furthermore, there is the ever-present anxiety that telomerase reactivation is a hallmark of most human cancers.”
