An Update on Uncoupling and Longevity for Humans

Uncoupling proteins (UCPs) govern the process of mitochondrial uncoupling, which changes the operation of the mitochondria in our cells to generate more heat and less of the cellular fuel chemical ATP. It's one of the mechanisms by which mammals regulate their body temperature. As for many processes that alter the behavior of mitochondria, uncoupling has an effect on life span, with more uncoupling usually leading to longer life spans:

Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example. It also appears to be important in calorie restriction, and therefore possibly important to longevity and aging.

The mitochondria are clearly very important in any consideration of aging, given that there are so very many ways to manipulate them to either shorten or lengthen life in laboratory animals. This is one of the reasons that any serious program of rejuvenation biotechnology has to include efforts to repair accumulated, age-related mitochondrial damage: there is an enormous weight of evidence telling us that mitochondria are a lynchpin in aging.

But back to uncoupling: there are compounds that promote uncoupling in mammals, such as DNP, but you can't just load up on an uncoupler and wait for the benefits to roll in. If your mitochondria produce too much heat for too long, you will simply roll over and die from something that looks a lot like heat stroke. Metabolism is a finely balanced machine, and taking it beyond its limits is easy to do once you bring this sort of process manipulation into the picture.

There exists a sizable amount of published work on uncoupling and longevity, and this field is, I think, helped by the fact that it borders on the study of calorie restriction, which is a heated area of research these days. A group that has published previously on human uncoupling protein variations and longevity in the past recently put out an open access paper on their research, which goes into more detail as to the findings.

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity:

In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner membrane transporters with variable tissue expression, which seem to function as regulators of energy homeostasis and antioxidants. In particular, these proteins uncouple respiration from ATP production, allowing stored energy to be released as heat. Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age.


Substantial evidence suggests that the ability of UCPs to reduce ROS and regulate energy utilization underpins the ability of UCPs to promote lifespan in various experimental models. In the present study we found that variants in UCP2, UCP3, and UCP4 significantly affect an individual's chances of becoming ultra-nonagenarians. The different localization of the proteins we found associated with longevity allows us to predict the areas where the uncoupling process may play an important role in survival at very old age.