When paraquat, which induces oxidative stress, is added to mouse fibroblasts in culture, CMA-active lysosomes are seen to move toward the perinuclear area. Similar activation was seen during nutritional stress.

Ana Maria Cuervo, Reprinted from Molecular Biology of the Cell (Mol. Biol. Cell 2004 15:4829-40; published online before print as 10.1091/mbc.E04-06-0477) with the permission of The American Society for Cell Biology

And as vital cells die, say, in the brain, the impact may show up gradually as Alzheimer's disease, Parkinsonism, or other chronic, age-related disorders.

Response Systems

The constant and intense push and pull exerted by hormones, growth factors, kinases and other signaling molecules makes it clear that evolution has used all the tricks in the book to control life – both normal and abnormal.

It’s also clear the biosystems that Nature has produced are not infallible, that they sometimes make mistakes, act badly, generally run down and slow down with advancing age. Although the common admonition is to age gracefully, sometimes we can’t, even though the body has complex defense mechanisms that help keep decay at bay – at least until the time of reproduction is past.

Of course, simply growing up is an enormously complex enterprise for any organism. Genes, cells and organs must work in exquisite concert to build tissues in just the right places, at just the right times. Not too big, not too small. Not too active, not too quiet.

Built-in response systems also activate when we’re sick or injured, for example, or when responding to the mating call. Hormones rage in response to stimuli. Immune cells signal among themselves to arm for combat at the first hint of infection. And blood platelets remain on guard, ready to respond by clogging up any breaches in the body’s exterior armor.

But aging is another story. The oxidative damage done by normal energy production inexorably causes DNA damage, harms membranes and even limits the lifespan of some cells. And as vital cells die, say, in the brain, the impact may show up gradually as Alzheimer’s disease, Parkinsonism, or other chronic, age-related disorders.

In efforts to learn how aging impacts various systems – and perhaps how to protect them –­ The Ellison Medical Foundation is supporting pioneering work by dozens of leading bioscientists engaged in fundamental studies of aging and its interplay with time.

Alfred L. Goldberg, for instance, is studying protein degradation that must occur if the cell’s protein-folding machinery makes errors. Accumulation of abnormal proteins poses a hazard to health, so Goldberg’s laboratory at the Harvard Medical School is looking into the details of how the ubiquitin-proteosome pathway gets rid of faulty proteins, and hoping to learn how it may relate to aging.

Peter G. Schultz, at the Scripps Research Institute, in La Jolla, Calif., is studying the molecules that respond by up-regulating the antioxidant response element. And Ao-Lin Hsu, at the University of Michigan, is working on heat shock factors and how they seem to play some role in controlling longevity.

As a result of these and other research projects, much is being learned about biological response systems. But the findings so far also make it very clear there’s still a lot to be learned.  One ultimate goal is to first understand, and then begin gaining control of, the aging process, to see if there’s any way to slow it down, or at least retard the onset of  chronic disabilities that are so strongly associated with aging.



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