Scientists have long thought that aging could be caused by molecular damage that accumulates in our bodies over the course of time. The damage is an unavoidable by-product of breathing oxygen and other metabolic processes that are necessary to life. Eventually, damaged cells stop working, or worse, adopt new functions that trigger cancerous growth or degrade important tissues in the brain, skin and other organs.
But as Melinda Wenner Moyer reports in the February issue of Scientific American, investigators have conducted several experiments over the past few years that challenge this so-called oxidative stress theory of aging. For example, a tiny mouselike creature known as the naked mole rat manages to live up to 30 years (about 10 times longer than a similarly sized mouse) despite accumulating a much greater level of oxidative damage in its tissues than other rodents.
These and other often surprising results have led to a boom in research on aging in the past few years, as investigators learn more about the inner workings of the cells at the molecular and genetic levels.
Scientific American spoke to Judith Campisi, a professor at the Buck Institute for Research on Aging and senior scientist at the Lawrence Berkeley National Laboratory, for a quick overview of the field. You can read more about Campisi’s research on cell senescence as one possible cause of aging in the August 2012 issue of Scientific American.
[An edited transcript of the interview follows.]
Why is it so hard to figure out what causes aging?
In many ways we already know what causes aging. We just don't know what causes aging in the kind of molecular detail that would allow us to intervene in large meaningful ways. It's not even clear that once we solve those mysteries we will be able to intervene in aging or dramatically extend longevity.
I started my career studying cancer. Look at all the things we have learned since the 1970s about how cancers form in the body. And yet, still the best cures we have for most cancers are sledgehammers. Biology is complex—and this is a reality that the public has to come to grips with and our legislators have to come to grips with.
I predict aging will follow the same trajectory as cancer research. Why is aging so difficult to figure out? It's because it's a really tough problem. I think it's tougher than cancer. The time has come to really wallow in the complexities.
How many different causes of aging do you think there will turn out to be?
I don't think there will be hundreds of causes of aging. But I don't think there will be just one, either, or we would have gotten a handle on it by now. It's sort of like asking me what the stock market would be tomorrow. I could give you an answer but you'd be crazy to believe me!
How about just a couple causes of aging?
Well, we know that there is molecular damage and what I will refer to as genetic damage—although that doesn't necessarily mean a mutation. By genetic damage, I am referring to both changes in the genes themselves as well as in the epigenetic switches that regulate how the genes are expressed.
Why does this damage occur? Basically, there are two main reasons: One, breathing oxygen is dangerous to your health. Your body makes certain harmful compounds just as a result of breathing oxygen. Two, the cells inside your body make mistakes when they divide. Most of the cells in your body are not dividing at any given time. Many have the ability to divide but don't. But when a cell does divide, it has to copy three billion base pairs of DNA exactly right. Inevitably mistakes happen and cells become damaged.
Between the damage from the oxygen you breathe, the food you eat, ionizing radiation, plus the normal damage from cell division, all that can drive aging—not just by causing cancer but also through cellular degeneration.
What would you say is one of the biggest mysteries of aging research?
Why do organisms with remarkable genetic similarity have sometimes remarkable differences in life span?
We know that for the most part, many of the processes that go on in the human body also go on in yeast and mice. Yet, yeast live a few days, a mouse lives about three years, and people live for decades. We really do not know what evolution has done to take basically the same genes and produce different life spans.
Is that where the naked mole rat comes in?
Yes. The mystery shows up even in species that are mouselike. The naked mole rat is more related to the mouse than to us—it looks like a mouse. And yet it lives for 30 years, or 10 times longer than a regular mouse. On top of all that, it has signs of oxidative damage that exceeds that of the mouse.
Now there are three ideas that scientists have come up with to try to explain why naked mole rats live so long: Maybe oxidative damage doesn't cause aging. Maybe naked mole rats are evolutionary oddities. And then my personal favorite, maybe it's not oxidative damage that is the problem but how the cell responds to the damage. But that's all speculative.
Any hope for treatments?
We really don't know whether it will be possible to substantially extend human life span. But we do think we will learn how to extend human health span, or the number of years that older people can live in relatively good health.
One of the protective mechanisms that we have evolved against cancer is called cell senescence. When a cell is damaged it either dies in a process called apoptosis or it simply stops dividing. That's cell senescence.
A few years ago, we learned that when cells opt to senesce they don't die. They persist. They increase with age. And they secrete inflammatory cytokines. So they can produce low level of chronic inflammation throughout the body with no obvious pathogen, and we think that is one of the drivers of aging. This is an example of an evolutionary trade-off. If you don't have the senescence mechanism, you die early of cancer. But if you do have this mechanism, you die later and miserably.
Do I think if I had a drug tomorrow that could kill senescent cells, it would make a human live for 5,000 years? No, I don't. But it might help attack several problems of aging—like Parkinson's disease or Alzheimer's disease—that involve a lot of inflammation. The idea would be not to treat one disease at a time, but to get at the underlying processes, like inflammation.