In the recent blog entry SIRT1, mTOR, NF-kappaB and resveratrol, I pointed out how “three different theories of longevity seem to be collapsing into one: 1. suppression of mTOR signaling, 2. activation of SIRT1, and 3. inhibition of expression of NF-kappaB. Activating SIRT1 does all of these things, and this seems to be accomplishable to some extent by taking resveratrol supplements.” Amplifying on that blog post here, I point out three additional theories of longevity that can be added to the list: 4. hypoxic signaling, 5. autophagy and 6. hormesis. SIRT1 can activate the pathways of each of these and can in turn be activated by resveratrol
One my early blog entries was and I have listed The Hypoxic Response in my treatise as a fifth additional candidate theory of aging. “Another cross-species pathway has been discovered that allows interventions to lengthen life in primitive organisms, C. elegans nematode worms in this case. The pathway is related to the hypoxic response, how cells respond to protect themselves when there is insufficient oxygen. It turns out that if the hypoxic response can be turned on when normal oxygen is present, nematodes live significantly longer. A recent research report indicates that this was experimentally accomplished by breeding nematodes that could not produce the protein VHL-1which destroys another protein called HIF which keeps the hypoxic response turned off when oxygen is present. Also, it appears that the cells in such long-lived nematodes are relatively free of lipofuscin and toxic age-related protein aggregations such as seen in Alzheimer’s, Huntington’s and other age-related diseases(ref). — As of yet, however, just how HIF works downstream to extend longevity is still unclear. The hypoxic response appears to operate in higher animals as well, including humans.”
Quoting the June 2009 publication Regulation of Hypoxia-Inducible Factor 2alpha Signaling by the Stress-Responsive Deacetylase Sirtuin 1: “To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinately increase production of protective factors. Hypoxia changes cellular metabolism and thus activates redox-sensitive as well as oxygen-dependent signal transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing deacetylase, selectively stimulates activity of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2
“In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly-regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes(ref).” Efficiency of autophagy tends to decline with aging and increasing effective autophagy is seen as a possible anti-aging intervention. According to the 2009 publication Regulation of the aging process by autophagy “During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In Caenorhabditis elegans, there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Recent studies have revealed that the same signaling factors regulate both aging and autophagocytosis, thus highlighting the role of autophagy in the regulation of aging and age-related degenerative diseases.”
The September 2009 publication SIRT1: Regulation of longevity via autophagy reports: “Recent studies have emphasized the importance of SIRT1, a mammalian homolog of Sir2 longevity factor, in the regulation of metabolism, cellular survival, and organismal lifespan. The signaling network interacting with SIRT1 continues to expand as does the number of functions known to be regulated by SIRT1. Autophagy is also an emerging field in longevity studies. Autophagocytosis is a housekeeping mechanism cleaning cells from aberrant and dysfunctional molecules and organelles. The extension of lifespan has been linked to the efficient maintenance of autophagic degradation, a process which declines during aging. Interestingly, recent observations have demonstrated that SIRT1 regulates the formation of autophagic vacuoles, either directly or indirectly through a downstream signaling network. — The interactions of SIRT1 with the FoxO and p53 signaling can also regulate both the autophagic degradation and lifespan extension emphasizing the key role of autophagy in the regulation of lifespan.”
My blog posting Hormesis and age retardation describes hormesis as a process of “challenging cells and body systems by mild stress resulting in them becoming stronger and resistant to aging(ref). The stress can be physical, chemical and even possibly psychological.” Exercise is an example. That blog entry reviews the science behind hormesis and some of its demonstrable anti-aging effects. Also, see my blog entry Stress and longevity for further discussion of how moderate stresses confer longevity.
Calorie restriction activating SIRT1 is a prime example of hormesis. The article Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart. “– moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.” And SIRT1 is important for cellular response to other forms of genotoxic stress(ref). The heat shock response is a well-studied example of hormesis, involving heat shock proteins. The 2009 publication Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1 states “Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA-binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.”
So, when researchers like Leonard Guarante or David Sinclair talk about the sirtuin SIRT1 affecting multiple longevity-related pathways, there is a lot of emerging science behind what they are saying. And there is a lot more to say about SIRT1 than I have covered so far. Up to this point I have talked about how six of the 21 theories and candidate theories of aging/longevity described in my treatise are implicated. But SIRT1 also links to several more of the aging theories, links I will discuss in future blog entries.