In the Part I post I described several recent studies relating to calorie restriction (CR), mainly ones exploring the pathways through which CR limits the development of cancers. I cite a background study on the somatotropic axis and a few additional recent studies here, with focus this time on the gene activation pathways that seem to be involved. And I touch lightly on how taking resveratrol supplements appears to mimic many of the effects of CR.
The somatotropic axis and IGF-1
As background, I begin by commenting on the somatotropic axis, a subject covered well in the 2005 paper Minireview: Role of the Growth Hormone/Insulin-Like Growth Factor System in Mammalian Aging. “THE SOMATOTROPIC AXIS, consisting of pituitary derived GH (growth hormone) and IGF-I, the main mediator of GH actions, is the key determinant of somatic growth and adult body size. Moreover, the GH/IGF-I system is involved in the regulation of puberty and gonadal function and influences body composition as well as structural and functional maintenance of adult tissues.” This pathway and its associated genes seem to be evolutionary conserved across a multiplicity of species including unicellular yeast, through insects, worms, rodents, and other mammals including humans.
The pathway seems also very relevant to aging. The key thing to note is that across many species including fruit flies, roundworms, mice and rats, inhibition of IGF-1 signaling is generally associated with smaller-sized animals and longer lifespans. Some people take human growth-hormone promoting supplements because they think it may extend their lives, but the evidence seems to point in the opposite direction. “– administration of GH is often advocated as an “anti-aging” therapy. In sharp contrast to these findings, GH deficiency, GH resistance, and reduced IGF-I signaling in mice are associated with symptoms of delayed aging and markedly extended longevity. Although most normal mice die at approximately 2 yr of age, hypopituitary and GH-resistant mutants often survive beyond the age of 3 yr and occasionally past the age of 4 yr, i.e. outside the range encountered in various laboratory strains of this species. — Association of reduced somatotropic signaling with extended longevity in laboratory stocks of house mice (Mus musculus) is robust, reproducible, and consistent across several mutants, genetic backgrounds, and diets (ref).” The same can be said for other more primitive species and “it seems entirely reasonable to expect that the involvement of these signaling pathways in the control of aging is universal and includes humans.”
From the viewpoint of the current discussion, there is strong evidence that the somatotropic axis, i.e., limiting of IGF-1 signaling is involved in the life-extending actions of calorie restriction. This is pointed out in several publications cited in the Part I post(ref). “The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1(ref).”
DAF-16, SMK-1 and PHA-4 It appears, however, that IGF-1 signaling is not necessarily the only or even the most important longevity-related pathway involved in calorie restriction. . According to a 2007 Science Daily posting: “– Initially, researchers thought that the effect of calorie restriction on aging was mediated through insulin-like signaling pathways in the roundworm Caenorhabditis elegans (C. elegans), but experiments by graduate student Siler Panowski in Dillin’s lab suggested otherwise. — In the worm, signals passed down the insulin/IGF-1 pathway regulate a DNA-binding protein called DAF-16 that belongs to what is called the forkhead family. It was believed that DAF-16 then regulated expression of genes associated with longevity. Dillin had also identified a co-regulator in the pathway called SMK-1 that apparently worked with DAF-16 to regulate longevity. — “When we asked whether DAF-16 and SMK-1 proteins were both necessary for CR-mediated longevity, DAF-16 turned out to be unnecessary but, somewhat surprisingly, SMK-1 was,” says first author Panowski. — Since 15 other forkhead-like factors are expressed in C. elegans, graduate student Suzanne Wolff and former post-doctoral fellow Hugo Aguilaniu, Ph.D., now an assistant professor at the Ã‰cole Normale SupÃ©rieure de Lyon, France, set out to determine if any of them teamed up with SMK-1 to delay aging in the CR-response. They did this by knocking out each gene separately and observing whether the genetically altered worms still showed enhanced longevity when calorie-restricted. — Loss of only one of the genes, a gene encoding the protein PHA-4, negated the lifespan-enhancing effect of calorie-restriction in worms. And, when researchers undertook the opposite experiment–by overexpressing pha-4 in worms–the longevity effect was enhanced. “PHA-4 acts completely independent of insulin/IGF-1 signaling and turns out to be essential for CR-mediated longevity,” says Panowski.” CREB, CBP, SATB-1 and histone acetylation Again alas , these are not the only pathways involved. The 2009 publication Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling points out “Here we report that hypothalamic expression of CREB-binding protein (CBP) and CBP-binding partner Special AT-rich sequence binding protein 1 (SATB-1) is highly correlated with lifespan across five strains of mice, and expression of these genes decreases with age and diabetes in mice.” The same publication states “drugs that enhance histone acetylation increase lifespan and reduce AÎ²42-related pathology, protective effects completely blocked by cbp-1 RNAi. Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway.” This landmark publication is well worth perusing and I quote a few other passages from it.
“Elucidation of mechanisms mediating lifespan extension and reduction of disease burden, including cancer and neurodegenerative diseases, by DR is a major goal of aging research . Recent studies have implicated sirtuins , SKN-1 , SMK-1 and PHA-4/Foxa , AMPK , RHEB-1 , daf-16/Fox1a , and HSF-1  in mediating lifespan extension by some, but not all ,, protocols of DR in Caenorhabditis elegans. However, a role for expression of these genes in mammalian lifespan has not been addressed, nor, with rare exceptions , has a role for expression of these genes in reduction of age-related pathologies by DR. The purpose of the present studies was to discover genes whose expression predicts lifespan and whose expression decreases with age and disease in mammals, whose expression is induced by DR, and whose inhibition attenuates life extension by several distinct protocols of DR. We report that among genes implicated in lifespan extension by DR or the insulin-like signaling pathway, only CBP meets these criteria.”
“In the present study we have discovered that DR induces a transcription factor, CBP, and additional factors that work with CBP to control the expression of other genes involved in determination of lifespan. When we blocked the DR-mediated increase in CBP and associated factors, we blocked all the protective effects of DR on lifespan extension, on the slowed rate of aging, and on protection against pathology in a model of Alzheimer’s disease. Further, in mice expression of CBP and a CBP-interacting factor positively predicted lifespan, and expression of both factors decreased with age and in diabetes. Finally, pharmacological manipulations that mimicked enhanced CBP activity increased lifespan and reduced pathology in a model of Alzheimer’s disease.”
“Mechanisms linking cbp-1 expression to increased lifespan and reduced age-related pathology are therefore of great interest. It is suggestive that all genes implicated in the present screens are either CBP or CBP-binding co-activators –. Similarly, genes recently implicated in mediating lifespan extension by DR, skn-1 and pha-4, also code for transcriptional factors that interact with CBP ,. Furthermore, transgenic overexpression of cbp-1 did not significantly increase lifespan (Figure S6), suggesting that effects of CBP on lifespan requires increased expression of other factors. Uniquely among factors implicated in mediating lifespan extension by DR, RHEB-1 is not known to interact with CBP . However, RHEB-1 mediates lifespan extension by intermittent fasting-induced longevity , which, in contrast to other protocols of DR (including those examined in the present studies), increases lifespan by reducing initial mortality rate, not by reducing age-related acceleration of mortality rate.”
A study cited in the Part I post implicates glucose metabolism in DR, in that healthy cells in-vitro lived longer and had better health indicators when deprived of a glucose nutrient, while the opposite was true of cancer cells(ref).
Epigenetic effects, Akt, mTOR, P16 and hTERT
The Part I post touched on how these too are involved in CR.
Resveratrol and calorie restriction
Resveratrol supplementation appears to partially mimic some of the longevity-promoting effects of CR, possibly via the IGF-1 channel, possibly via other mechanisms. This is the probably-good news for us longevity aficionados. In a mouse study: “We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR(ref).” There is a lot more that can be said about this subject, however, and that will be the subject of a future post.
Wrapping it all up
Researchers are developing ever-better understanding of the underlying molecular/epigenetic mechanisms of CR. Further – and that is what is most exciting – it appears that with resveratrol and new resveratrol homologs, we may already have a practical anti-aging intervention that takes advantage of the CR pathways nature have given us. And, stay off of the glucose!