Conformational Changes Observed in GAPDH in ALS Mouse Models

Using a BisANS assay developed by our (Richardson & Regnier) group, we studied the effect of oxidative stress on protein conforma- tion in vivo using mouse models of ALS. One protein showed major changes in BisANS labeling in all ALS models tested, GAPDH. The changes in BisANS were correlated with a loss in enzymatic activity. The tetrameric structure of GAPDH is shown with the active site of the enzyme in black and circle


One attractive explanation is that when animals are diet-restricted, they allocate available resources away from reproduction and toward somatic maintenance.

 

Metabolism and Caloric Restriction

Given the complexity of the biosciences, it’s no wonder medicine and the healing arts seem to progress so slowly.  But in reality, the learning curve in the life sciences – particularly in genetics and molecular biology – has gone exponential, straight up. A fascinating array of new tools, techniques and a deeper understanding of how life works are combining to force a revolution in medical practice. Targeted therapies are taking aim at cancer. Surgical, pharmaceutical and mechanical interventions are changing the landscape of heart disease. And pioneering studies of the biochemical networks that keep life going are offering the first real glimpses into the aging process.

There is, of course, much interest in aging, since so many Americans (remember baby boomers?) are facing the vagaries of old age, and would love to do something about it. Aging gracefully is especially hard if you don’t feel well, so increasing effort is going into making the later years of life less burdensome, more comfortable and more active. We already know enough to discourage smoking, improve diets, avoid being couch potatoes and all that. But the very nature of aging is still an enigma, and research is focusing on why we age, and what might be done about it.

For example, increasingly detailed studies of the mitochondrion, life’s major vehicle for energy metabolism, suggest it lies at the heart of the inexorable process of aging. As one’s mitochondria gradually poison themselves while doing their duty, system after system – brain, muscle, kidney – begins to weaken. eventually one or the other fails, and life ends.

How that happens is being pursued by many Ellison scholars.  One of them, C. Ronald Kahn, at the JoslinDiabetesCenter and the HarvardMedicalSchool, has created the interesting FIRKO (fat insulin receptor knock-out) mouse, engineered so its fat cells lack the normal insulin receptors.

The resulting animals dine on normal amounts of food, yet still grow up lean, resistant to diabetes and also live longer than usual, apparently because of altered mitochondrial metabolism. This points toward glucose metabolism as an important factor in aging, and perhaps in the diseases that accompany old age.

Similarly, Pankaj Kapahi, at the Buck Institute for Age Research, is looking at energy balance, food restriction and even the evolution of aging. Results from Kapahi’s team suggest that aging is the result of natural selection favoring robustness in early life – the reproductive years – at the expense of deteriorating later.

Bruno Conti, at the Scripps Research institute, is going beyond caloric restriction in focusing on aging. he’s studying temperature, showing that the lifetime of mice can be extended simply by keeping them chilly. In other words, despite diet, if the animals’ core body temperature is kept slightly below normal, lifespan can be extended, almost matching what’s seen in caloric restriction studies. Again, this points to the mitochondria, with lower temperatures reducing mitochondrial activity, helping extend lifespan.

Oddly, though, measurements show that being chilly doesn’t reduce the animals’ production of damaging free radicals, which are thought to play some role in age-related decline.  So, at this point, even though the mystery of aging seems to be yielding to research, it’s still a difficult puzzle.