Why do we age? It’s more than just a philosophical question; it’s a puzzle that has frustrated scientists for decades. Currently, the most accepted hypothesis is that aging is the result of accumulated damage to our cells during our lifetime. “Accumulated damage” encompasses a variety of things that can go wrong, including DNA mutations, problems in the way molecules such as proteins are built, or abnormal interactions between molecules. Over time, the damage interferes with the body’s ability to maintain itself the way it used to, and the process we call “aging” occurs.

Click on the picture for a bigger version. Multiple external and internal factors can lead to the formation of free radicals and cell damage, which accelerates aging.

It sounds like a great hypothesis, but how can we prove it, and how can we measure accumulated damage? Damage can be caused by a number of factors, and the types of damage that can occur varies wildly between species and even between individuals of the same species. To make matters worse, exposure to certain environmental influences or toxins can accelerate aging. For example, overexposure to UV light from the sun can increase signs of aging in skin cells, and studies have shown that smoking can also accelerate aging. How can scientists study something with so much variability and uncertainty? A recent fruit fly paper published in eLife by the Gladyshev lab describes a new way to study damage accumulation. Instead of measuring the damage itself, they measure the byproducts of cellular metabolism as a proxy.

You see, even if we were able to reduce exposure to environmental toxins, we’d still get older. That’s because unfortunately, even our bodies are working against us. Our cells have metabolic processes, which are the life-sustaining chemical reactions that are needed to keep them alive and reproducing. The small molecules that are produced by these reactions (called metabolites) are usually important for the cells; they could be fuel for energy, signals for growth or reproduction, or even necessary for defenses and interactions with the environment. Unfortunately, these processes also create toxic byproducts such as reactive oxygen species (also known as free radicals). These byproducts cause damage and have often been associated with many age-related diseases such as cancer, heart disease, and Alzheimer’s disease.

To test the idea that accumulating metabolic byproducts can lead to aging, the authors of this study used a new method called “metabolite profiling” to measure the amount of metabolites in flies as they aged. (If you’re interested, the technique they used is called liquid chromatography mass spectrometry). They first found that the diversity of metabolites increases with age. This suggests that mistakes were being made during the metabolic reactions, causing new types of byproducts to appear that can damage cells. Additionally, a subset of metabolites accumulated with age, which may indicate that these byproducts are not being sufficiently cleaned up by maintenance processes in the cells. The authors found that many of these had previously been identified as damaging, directly confirming that accumulating toxic byproducts is correlated with aging.

Finally, the authors also used a calorie-restricted diet to extend the lifespan of a group of flies (although it’s not yet understood why, a severely restrictive diet can increase lifespan in many model animals, including mice and rats. It’s not recommended for humans, however, because there are unpleasant side-effects). Most interestingly, when the authors compared metabolite accumulation in normal flies versus the lifespan-extended flies, they showed that the metabolite accumulation was slower in the longer-lived flies, corresponding with the slower progression of aging.

So how can these findings help us? This paper supports the hypothesis that accumulation of damage leads to aging by showing that metabolites accumulate at a rate that corresponds with relative age in fruit flies. Because most species share the same cellular metabolic processes, these results are relevant to mammals. The next step will be to identify particular types of metabolites and determine how they contribute to aging in flies and mammalian models. The authors of this paper already did some of the legwork. They found that many of the metabolites that differed between the lifespan-extended group and the normal group of flies were associated with processes for using and storing energy from fats and proteins (not surprising considering the flies were on a strict diet). The authors suggest that changing these metabolic processes through diet may have compensated somehow for the accumulation of toxic byproducts. Future research may be able to expand upon these findings, and perhaps even figure out a way to interfere with these processes to slow or alter aging. I just hope I live long enough to see it!

Reference:

eLife, 3 DOI: Avanesov A.S., Kerry A Pierce, Sun Hee Yim, Byung Cheon Lee, Clary B Clish & Vadim N Gladyshev (2014). Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation,DOI: http://dx.doi.org/10.7554/elife.02077

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