By Ina Chen ‘14 and Jonathan Zhou ‘14, thurj Staff

It is common knowledge that mental abilities decrease with age. Over the years, many people have attempted to understand the processes of aging and develop methods to delay the debilitating conditions brought on by old age. Recently, advancements in the field of biology have revealed more and more about the underlying mechanisms and causes of aging. Recent research in the lab of Harvard professor Joshua Sanes continues this trend by providing us with new insight on how aging occurs. Sanes, a professor of Molecular and Cellular Biology, investigated the relationship between caloric restriction and exercise in mice and age-related conditions such as neuron synapse decay. Sanes sat down with thurj to discuss his research, future directions, and the implications of his findings.

Previous work has been shown that caloric restriction improves the cognitive function of lab mice. However, the cause of this effect at the cellular level remained unknown. One hypothesis, which attributed the cause to neuron death, has largely been disproven. Thus, given that caloric restriction and exercise seem to delay age-related mental decline, Professor Sanes’s lab decided to investigate any impact these two conditions might have on the deterioration of synapses in mice. In particular, Sanes’s group studied neuromuscular synapses, the junctions that form between the axons closest to the muscle fibers (motor neurons) and the muscle fibers themselves. As mice age, these synapses, which form early on in axon development, disassemble, and the junction deteriorates so that the axon and the muscle fiber no longer form a strong connection. Sanes’s lab monitored mice of up to 24 months of age that were put on caloric restriction by controlling intake of carbohydrates while maintaining a balanced diet. The researchers found that these mice experienced much less synaptic decay than mice that were not put on the diet. A similar difference was observed between more active mice and more sedentary ones. Even more surprising, exercise in older mice had the effect of reversing the decay of neuromuscular synapses, effectively returning the junctions to a younger state. Although researchers looked at the motor neurons because their relatively larger size allowed them to be easily studied, the effects of caloric restriction and exercise were also observed for brain functions not carried out by motor neurons, such as cognitive functions, memory, and behavioral health.

What do these findings mean for us? Although laboratory studies conducted on organisms such as mice, worms, and flies have repeatedly confirmed the effect of caloric restriction and exercise on extending the health span of these organisms, little evidence currently exists showing how much this carries over to humans. Still, there is little doubt that recent lifestyle shifts have had a negative impact on the health of individuals in our society. The average human life span has increased as technology has made life easier, cures for diseases have been discovered, and diet has been improved. However, it seems as if we have reached a point where human life span in the developed world is leveling off and is possibly heading in a downward trend as life-style related conditions such as obesity begin to plague our health. Although this may seem odd in the context of evolution, Sanes described two hypotheses that scientists have come up with to explain this phenomenon. One attributes aging from food intake to the oxidation that occurs when our bodies process food. The other comes from an evolutionary biology perspective and posits that individuals who are able to delay the end of their reproductive periods—and thus their youth—during times of food scarcity are selected for over individuals who cannot. But because the caloric restriction imposed on the test organisms in this research is not the same as food restriction, which would not necessarily provide a balanced diet, the real reason has yet to be found. Of course, these missing pieces have not hampered the efforts of drug companies to develop therapies that might counteract the effects of unhealthy lifestyles.

Professor Sanes, however, is concerned about the direction the pharmaceutical industry is taking with what seem to be anti-aging miracle drugs: “One of the reasons for this huge pharmaceutical interest in caloric restriction is that I think it is generally understood that there’s an epidemic of eating too much, that it’s truly wrecking people’s health. But the chances of getting people to eat less are extremely low. Therefore people want some kind of drug that can be a painless way to produce this effect.” Professor Sanes does not want the results of this research to become the basis for therapy treatments to prolong life span; there is still too much that remains unknown about the whole process. While it was shown that caloric restriction and exercise can have a reversing or halting effect on the deterioration of synapses, researchers both in his lab and elsewhere are still trying to uncover the mechanisms that drive these effects. Before these details are fully understood, it would be risky and difficult to artificially replicate the effect of exercising or caloric restriction in a drug. However, this has not deterred companies from trying. One such company, Sirtris Pharmaceutics, is based here in Cambridge, Massachusetts. Sirtris specifically targets conditions related with aging by developing drugs similar to certain molecular intermediates that would mimic the effect of caloric restriction.

Whether in the pharmaceutical industry or in the labs here, new research discoveries will continue to help us create a clearer picture of the aging process. In the Sanes lab, future research will seek to answer questions such as whether or not synaptic aging is accelerated after the delay of synaptic deterioration, what the extent of exercise-related rejuvenation is, and to what degree the trends observed in laboratory organisms carry over to humans. To learn more about these questions, they will look into changes that take place in gene controls, gene expression, and molecular pathways. Perhaps one day, answers from this research will replace the current mysteries and eventually lead to therapies that can manipulate our aging process. But until then, we should stop and think: with all of these findings pointing to the benefits of a healthy lifestyle, will we learn to make the simple acts of watching what we eat and hitting the gym every now and then a priority?

To Professor Sanes, it seems like “people would like to live longer, but there’s no way that they are going to stop eating.” But decaying neural function as a result of eating more and exercising less than we need is definitely some food for thought.




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