Interviews on Aspects of Aging with Judith Campisi and Dena Dubal

Today I'll point out a pair of interviews with researchers Judith Campisi and Dena Dubal, in which they discuss quite different aspects of aging. Campisi's research has a heavy focus on cellular senescence in aging. Cells become senescent constantly in the body, most because they hit the Hayflick limit on replication imposed upon the somatic cells that are the overwhelming majority of cells in our tissues. Cells can also become senescent because of damage, or encouraged into senescence by the signaling of other, nearby senescent cells. Once senescent, cells are normally quickly removed by the immune system or programmed cell death mechanisms, but the balance between creation and destruction is disrupted with age, allowing the number of senescent cells to grow. These cells secrete a potent mix of signals that produce chronic inflammation and disruption of tissue structure and function, an important contribution to degenerative aging.

Dubal, on the other hand talks about the well known gender difference in longevity. There are many, many theories as to why women life longer than men. It is a feature of species with mating patterns like our own, so it is unlikely to result from anything particularly human, such as median male versus median female lifestyle choices peculiar to our species, such as smoking. Evolution interacts with mating strategies to favor women in this way. Under the hood, identifying the mechanisms involved in the comparative longevity of women suffers from the same issue as many other areas in aging - everything changes with age! While the principle differences between male and female tissues are well known and easily enumerated, it is very challenging to link those fundamental differences to specific changes in the pace of aging or late life mortality. This remains an actively debated topic.

Why Do We Get Old, and Can Aging Be Reversed?

Campisi: Many of the processes that happen during aging really happen as a consequence of the declining force of natural selection. That is, there was no natural selection for these diseases. The process we study, cellular senescence, it's now clear - and certainly in mouse models - that this process, the cellular process, drives a large number of age-related diseases, everything from macular degeneration, to Parkinson's disease, cardiovascular disease, and even late-life cancer, but it evolved to protect young organisms from cancer. So we certainly don't want to stop it when we're young.

Senescence is a state that the cell enters, in which it adopts three new traits. One of them is it gives up almost forever, almost forever, the ability to divide. It will tend to resist dying. And most important, it tends to secrete a lot of molecules that can have effects on neighboring cells, and also in the circulation. Not that many cells have been studied when they become senescent. And almost everything else we know about senescence is slowly changing as we learn more and more about different cell types and different ways that cells enter senescence.

There are still very few of them even in very old and very diseased tissue. A few percent at the most. So why do people think this has anything to do with aging? That has to do with the third thing that happens when cells become senescent is they begin to secrete a large number of molecules that have biological activity outside the cell. And that means that those senescent cells can call immune cells to the site where they are, it can cause neighboring cells to fail to function. And it basically causes a situation that is classically termed chronic inflammation.

If you eliminate senescent cells, it is possible to do one of three things to an age-related pathology: You either make it less severe, or you postpone its onset, or - and this is, of course, the one we all love - in a few cases, you can even reverse that pathology.

Dubal: in every society that records mortality across the world, women live longer than men. From Sierra Leone, where lifespan is lower, to Japan and Sweden, where lifespan is much longer. But here's a really interesting piece of information: When we look historically across multiple countries and societies, at times of extreme mortality, like famine and like epidemics, the girls will live longer than the boys and the women will live longer than the men. And this, this really suggests to us that there is a biologic underpinning for female longevity, because even when there is very high and equal stress in the environment with very high mortality, the girls are outliving the boys and the women are outliving the men. There's some very, very sad and really remarkable times that, that demonstrate this including the Irish famine and many, many other examples in our world history.

If we think about this, biologically, why there could be sex differences and human longevity. One has to do with chromosomes, our genetics, our genetic code, and every single one of our cells in our bodies. And that is that female mammals and certainly female human mammals have two X chromosomes in every cell. One of them is inactivated during development, but there are two X chromosomes, and that is the sex chromosome complement of women and girls. In contrast, boys and men have one X and one Y chromosome. And so here already at the outset, there is a very clear and striking difference in our genetics. And so with this difference, and XX in females compared to XY in males, there, there arises for biologic reasons, for sex differences in longevity. One is that in males, there's a presence of a Y. And it is thought, although not experimentally shown, that maybe there are toxic effects or deleterious effects of the presence of a Y chromosome.

Further, all the mitochondria in all of your cells are inherited from our mothers. So in the process of cellular division and the creation of a zygote, mothers pass on their mitochondria, not fathers. And so this becomes really important because mitochondria can only undergo evolution in a female body. Males will never pass their mitochondria on. And so at the end of the day, what that predicts is that mitochondrial function is more evolved to female physiology, when compared to male physiology. And this may make a difference with aging when things begin to go awry. The female cells may be more fit because their mitochondria are more evolved to the female cells compared to male cells.

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