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The Detailed Progression of Aging is Always More Complex than Previously Suspected

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Posted 15 September 2021 - 10:22 AM

Aging has comparatively simple root causes, forms of cell and tissue damage that accumulate as a side-effect of the normal operation of metabolism. These comparatively simple causes take effect on a very, very complex system, however. The result is an intricate web of interacting consequences, and ultimately a dysfunctional, failing mess in which it is very hard to pinpoint which of the countless observed mechanisms are actually important. The complexity of the outcome is a result of the complexity of a living organism, not of the complexity of the root causes of aging. Metabolism is incompletely understood, and for so long as that is the case, inspecting the progression of aging will continue to reveal new subtleties. This is why interventions should focus on the causes of aging, far better understood at the present time, and not on manipulating later stages of the process, much of which remains a dark forest.

Researchers have made a surprising discovery about the connection between protein shape and mitochondrial health, providing a piece of evidence for yet another theme in aging research: it's always more complicated than we thought. Proteins within the mitochondria are intricately involved in mitochondrial function, and are protected by the mitochondrial unfolded protein response (UPRmt). When proteins misfold in the mitochondria, which can be caused by external threats like pathogens or mitochondrial toxins, the UPRmt gets activated which helps restore protein shape and function. Past research on the microscopic worm C. elegans has demonstrated that boosting the UPRmt during development contributes to better mitochondrial health and a longer lifespan for the worms.

Consistently, pharmacologically boosting UPRmt has been shown to slow down diseases with mitochondrial dysfunction, such as Alzheimer's. The new research has found that activating the UPRmt in adult worms has the opposite effect: adult worms with a boosted unfolded protein response have worse health and a shorter lifespan. Digging into the details of this surprising outcome led the team to examine the mitochondrial permeability transition pore. Most of the time this pore is closed, keeping the interior of the mitochondria separate from the rest of the cell. Under stress, though, it opens to release calcium into the rest of the cell, signaling that it's time to cut its losses and induce cell death. It turns out that methods to boost the UPRmt in adult C. elegans are caused indirectly - the UPRmt is initiated in response to the opening of the transition pore. While the UPRmt is busy trying to clean things up, the signals coming from the opened pore are too strong for the cell to ignore and result in cell death. Researchers think this is what contributes to the early death of the adult worms.

Research in C. elegans forms the basis of much aging research, but what does this mean for efforts to boost health and prevent disease in people? While the mitochondrial permeability transition pore is already implicated in conditions like stroke and heart attack, the role of the UPRmt is not as well understood. Researchers liken the UPRmt to inflammation, which has a specific purpose and is useful under some conditions, but causes damage under others. One possibility is that, in a stressed cell, the UPRmt uses valuable cellular resources, hastening the already inevitable cell death.

Link: https://www.buckinst...han-we-thought/

View the full article at FightAging

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