Even the Longest Known and Most Studied Longevity Mutations are Poorly Understood
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One of the arguments for focusing on repair strategies for reversing aging rather than manipulation of metabolism to slow aging is that metabolism is fantastically complex. Researchers don't have anywhere near enough understanding to safely alter metabolic operation in desired ways, and even simply trying to replicate aspects of the known and easily studied altered state of calorie restriction has proven to be very challenging. So there is no comprehensive plan on how to slow aging in this way. We can compare that absence to the existence of the comprehensive SENS plan on how to repair damage to reverse aging - and in that case we don't need to know anywhere near as much about how metabolism works. We just need to identify the damage and determine how to produce means of repair, and this goal has already been achieved.

An example of the complexity of metabolism and its interaction with the processes of aging is provided by this research, which illustrates that there is still much to be cataloged and understood in one of the longest known longevity mutations:

Twenty years ago it was discovered that loss of insulin/IGF-1-like signaling (IIS) - such as occurs in daf-2(-) mutants - dramatically extends longevity in the nematode C. elegans via the FOXO transcription factor DAF-16. Under favorable conditions, DAF-16 remains cytosolic and transcriptionally inactive; under stress, it is driven into the nucleus, leading to both up-regulation and down-regulation of large sets of genes, referred to as Class I and II, respectively. Identifying these genes and their functions is key to understanding the molecular and biochemical determinants of aging and longevity. While several studies have been performed to determine the genes regulated by DAF-16, agreement on the identity of targets has been limited to a relatively small number of top responders. Moreover, recent results have made it clear that while DAF-16 is responsible for the activation of Class I genes through the DAF-16 binding element (DBE), it does not interact directly with the upstream promoter regions of Class II genes, leaving the down-regulation of the latter in IIS mutants unexplained.

To address these issues, we first performed a careful meta-analysis of all available genomewide expression profiles with DAF-16 active (nuclear) vs. inactive (cytosolic or null). We reprocessed relevant raw data from various laboratories, and used a voting algorithm developed specifically for this purpose to construct a consensus ranking of all C. elegans genes in terms of their responsiveness to DAF-16. This allowed us to redefine Class I and Class II targets with unprecedented sensitivity and specificity. Next, using a combination of computational and experimental methods, we discovered that the little-studied transcription factor PQM-1 regulates Class II genes (and Class I to a lesser extent), via the DAF-16 associated element (DAE). [PQM-1] binding is strongly associated with both proximal upstream DAE occurrence and responsiveness to DAF-16. Indeed, a reporter gene assay confirmed that PQM-1 activates transcription in a DAE-dependent manner.

Next, we investigated whether and how PQM-1 subcellular localization depends on IIS status. [We] found that the nuclear presence of PQM-1 and DAF-16 is controlled by IIS in opposite ways. A model emerged in which both the DBE and the DAE contribute to the expression of Class I genes, while Class II genes are exclusively controlled through the DAE. Under normal conditions, the DAE-dependent transcriptional activation of Class II genes by nuclear PQM-1 enables growth and development. Upon acute stress, PQM-1 leaves the nucleus while DAF-16 enters. The nuclear exit of PQM-1 causes expression of Class II genes to fall in response to loss of activation through the DAE; at the same time, DAF-16 moves into the nucleus, where its binding to the DBE in the upstream promoter region of Class I genes activates a stress response in the cell.

Link: http://www.impactaging.com/papers/v6/n1/full/100628.html

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