Thursday, March 28, 2013

Looking for a Way to Cure Aging

Looking for a Way to Cure Aging


Prof. Linda Partridge Discusses Her Research on Senescence

By , About.com Guide
Source: biotech.about.com

Updated December 06, 2012
 
At the 2012 European Molecular Biology Organization (EMBO) meeting, Dr. Linda Partridge talked about the connection between aging and the biological pathway for nutrient sensing. Nutrient sensing is not at all the same as nutrition in the sense of what foods are healthy to eat. Nutrient sensing has to do with the protein and gene interactions that enable the body to sense what we eat, and respond by stimulating growth and activating various metabolic pathways. It seems the same proteins and genes involved in this process also regulate the aging process, also known as senescence.

The Connection Between Nutrients and Aging

There appears to be close connection between this nutrient sensing pathway and the complex biological process of aging. It has been known for years that severe diet restriction, basically a very low calorie diet that provides essential nutrients, actually extends the life of most animals. The observation that limited calorie diets extend the life of lab mice and rats by more than 25% was first published in 1935. Later research found a similar phenomena occurs in yeast, fruit flies, rats, and monkeys (although one recent study has produced some conflicting results regarding the situation with monkeys).
 
Long term controlled studies of caloric restriction on humans is not available for obvious reasons. However, Dr. Partridge did mention that she has met a few people attempting to live on a calorie restricted diet and, while she didn't know the effect of it on their health, they were not very happy people. A restricted regimen of calories similar to what is provided to mice and rats in the lab is very severe.

The Aging Program

While many researchers have looked for general metabolic reasons for the life extension response to caloric restriction, Dr. Partridge has focused on trying to work out the essential genetic interactions that produce this effect. What she and a few other researchers that have taken this gene-based approach seem to have discovered is that there appears to be an underlying biological process that produces the aging effect.

Aging manifests as a very complex constellation of conditions including wrinkled dry skin, declining eyesight, poorer hearing, arthritis, the development of cataracts, and with these physical changes, a sharply rising incidence of serious health conditions such as cardiovascular disease, diabetes, dementia, and cancer. The leading risk factor for these disease and several others is simply age. It seems that all the body’s systems are falling apart and most people think of this as a general wearing out of the body. However, the science indicates that an underlying genetic program may be at the root of these age associated changes.

Genetics Influences Aging

Dr. Partridge suggested that perhaps it shouldn’t be surprising that there appears to be very fundamental biological controls at the core of aging. There is no simple explanation why mice typically live barely 2 years while baleen whales, another mammal, lives over 200. While there is a vague correlation between animal size and life span across all animals, it is certainly not consistent or predictable. Larger dogs have shorter life spans than small ones. Most rodents have very short life spans but some porcupine species and the ugly naked mole rat have lifespans of more than 20 years. The Brandt’s myotis bat can live 40 years. Outside of mammals, many birds have quite long lives. Parrot life expectancy is on par with humans. Clearly, there is some underlying genetic control managing the aging program.
 
Finding Aging Genes

Dr. Partridge's colleague David Gems made the first age-related gene breakthrough when he found the aging process could be significantly altered in nematodes worms with a mutation in just one gene. In fact, he actually found that, if any of three different genes were mutated, lifespan of the worms increased. These genes were for components of the insulin receptor pathway, the series of interacting proteins that respond after the hormone insulin triggers its receptor on the cell membrane. Here we have the connection between aging and nutrient sensing—insulin controls food metabolism.
 
Overlap Between Aging Genetics and Metabolism

Dr. Partridge’s lab extended Dr. Gems' work by showing that similar genetic alternations in flies and mice also extend the life of these animals. Further, they showed that the effect was very similar to the extension that occurs with dietary restriction.
 
Even more interestingly though, her lab went on to show that in fruit flies, and preliminarily in mice, life extension does not correlate with limiting all calories but just protein. Further, it seems to be just certain amino acids that make up proteins, ones that are essential, that seem to be responsible for the life extension effect. Of course, the specific requirements are not so simple and the Partridge labs are in the midst of working out the details. However, what is clear is that regulators in the insulin sensing pathway cause significant changes on the overall aging process for both flies and mice.

The Problem with Aging

From Dr. Partridge’s perspective, however, the practical goal of her work is not really to extend the human lifespan. To go back to the previous point about how aging affects us in so many ways, the critical aspect of her research is not that the flies and mice just live longer, but that the effects of aging are all reduced. The animals stay healthier longer. The characteristic markers for aging, such as osteoporosis, cataracts, graying hair, and even cancer and cardiovascular disease, are all delayed. This is the eventual medical goal. In Dr. Partridge’s words, “the real aim is simply to keep people healthier as they age.”

Dr. Partridge explained that the national health systems can’t cope with the massive demographic changes happening in countries such as the UK. More and more elderly are showing up in hospital emergency rooms with complex health conditions. As the healthcare system is inundated with an increase levels of age-related illnesses, she sees the system collapsing. It is a bleak perspective that is, unfortunately, based in solid statistics resulting from "massive demographic changes." To fix it, the goal is that "people age well and then die quickly."

Curing the Effects of Aging

She hopes that her and her colleagues' work will soon be able to translate into treatments that ameliorate the situation. She notes that the science certainly indicates there is the possibility of a "broad spectrum preventative" that will address age-related illness. However, she is not overly optimistic. Any new drugs take so much time and resources for development that it would be 20-30 years before they would be available. Also, aging itself is not a recognized a disease, so approvals for any new potential drugs would have address a health condition in specific population, for example diabetes or metabolic disease.

Dr. Partridge's hope really is in finding new activities for already approved medications or candidate drugs that passed safety trials. Rapamycin, for example, an immunosuppressant used to prevent rejection of organ transplants, affects the mTOR protein which is the central regulator in the insulin receptor pathway (actually TOR in mTOR stands for Target of Rapamycin). The drug is known to extend the life of mice and it may have more broad utility. Of course, rapamycin also has serious side-effects. It increases the risk of diabetes and, as an immunosuppressant, infections. Metformin, a diabetes medication, is another drug that affects a component of the same insulin receptor pathway and has been shown to extend the life of mice.
 
What's the Outlook for an Aging Therapy Soon?
 
Dr. Partridge confided that, although she knows of some researchers who take rapamycin, she believes it is "crazy" at this point since the doses and side effects are really not clear. On the more pedestrian side, however, she also noted that, in addition to its cardiovascular benefits, daily aspirin has recently been shown to reduce cancer risk with aging and also appears to interact with mTOR in the insulin sensor pathway. Dr. Partridge said she does take aspirin daily basis.

With regard to finding new uses for failed candidate drugs, the major challenge she sees with evaluating these medications is working with the pharmaceutical companies who own them. She mentioned she has some productive collaborations with Pfizer and GlaxoSmithKline but, generally, academic/commercial interactions are difficult to initiate. She mentioned that she has outlined many potential experiments with scientists from various companies at one meeting or another and then, after returning to the lab and trying to coordinate the legal details to transfer materials, the whole process get mired down and the project never gets off the ground. To make real progress in the near term, she believes industry really needs to change how it works with academics.


Professor Linda Partridge is a Founding Director of the Max Planck Institute for the Biology of Ageing at the University of Cologne, and the Director of the Institute of Healthy Ageing at the University College of London. I had the exceptional opportunity to speak with her at the 2012 European Molecular Biology Organization (EMBO) meeting.