Hypothalamic Sirt1 as the Key to Longevity

Settling the Debate

Review Paper by:Paola Caballero

RISE Program UPR-Cayey

Introduction

Sirtuins are a family of proteins that have been identified in various animal species.

conserved through a long line of animal species

NAD+-dependent deacetylase proteins

Guanine

Acetylgroup

Introduction

The first component of the Sirtuin genes that code for sirtuin proteins was identified in yeast as was named silent mating type information-2.

regulates various metabolic pathways, which include life span and aging regulation

Silent mating type information-2 homolog (SIRT1) in mammals is equivalent to Sir2 in yeast.

The idea that SIRT1 could be the key to longevity has become very controversial.

Sirtuin 1

Silent mating type information-2 homolog (SIRT1)

deacetylase protein

Mainly found in: nucleus and cytoplasm

Silences histones

Primary role: the regulation of non-histone substrates like transcription factors.

Regulate systemic and cellular adaptation in response to various types of stresses.

Activation of PGC-1a and FOX

proteins

Gene Transcription

Mitochondrialbiogenesis

Gluconeogenesis

Stress resistance

Factors that up-regulate

Sirt1

Aging

The process of aging is a matter of much interest in the field of science.

Many diseases are the result of aging, hence learning as much as possible about this process is imperative in order to understand how to slow, prevent or even avoid aging-related diseases.

Aging Oxidative StressMacromolecules

and cells are oxidized

Many free radicals

produced

Damagebiologicalstructures

Compromisecellular

functionsShorten lifespan

SIRT1 in Aging

Cronic Oxidative Stress

The activity of SIRT1 diminished considerably in lung cells that were treated with cigarette smoke extract and hydrogen peroxide in a dose and time dependent manner (Caito et al. 2010).

It was also found that SIRT1 leaves the cell nucleus under these conditions, thereby failing to regulate targeted genes and proteins.

Exercise

Exercise has been identified as a mechanism to increase the activity of SIRT1 in human skeletal muscle (Gurd et al. 2010).

When the samples were analyzed after the 6-week training, the activity of SIRT1 protein was found to have increased, which correlates with the increase of the muscle’s oxidative capacity, but the protein count had decreased.

Low Nutritional Availability

One of the most common strategies used in studies of life span extension

Implies lowering caloric intake below the levels for maximum development and fertility but still managing to be considered nutritionally sufficient

CR has a stress effect in the body. In turn, this stress activates the body’s survival mechanisms.

LowATP

HighNAD+

HighSIRT1

Activity

Deacetylation of

PGC-1a, ERRa, FOX01 IncreasedMitochondrial

activity and biogenesis

ImprovedMetabolism and

diseaseprevention

Sirtuins as regulators of metabolism

Controversy

Caloric Restriction appears to be the efficient approach to achieve longevity.

Such studies focused on activity of SIRT1 in tissues like skeletal muscle, kidney, and liver.

Hypothalamic SIRT1

The study made by Ҫakir and colleagues (2009) provides intriguing insight that could overthrow this hypothesis by analyzing hypothalamic SIRT1.

According to Ҫakir’ study, caloric restriction, instead of extending life span, actually shortens it by causing obesity and the diseases that relate to it.

Hypothalamus

ARC/PNV nuclei

Othernuclei

SIRT1 SIRT1

DeacetylatesFOX01

Suppressed POMC, an appetite regulator

Increase in AgRP,which stimulates appetite and food intake

Another look at the hypothalamus

The study realized by Satoh and his colleagues (2013) has recently given substantial proof that protein Sirtuin 1 (Sirt1) plays an important role in longevity and the process of aging

Transgenic BRASTO mice that overexpressed Sirt1 specifically in the dorsomedial and lateral hypothalamic nuclei

Hypothalamus

ARC/PNV nuclei

DMH/LHnuclei

SIRT1 SIRT1

DeacetylatesNkx2-1

target gene Ox2r

•sympathetic nervous system ultimately skeletal muscle function•preserves quality of sleep•increase of physical activity, body temperature and oxygen consumption.

Summary

Aging, exercise and caloric restriction produce oxidative stress, in turn activating the homeostatic role of SIRT1

In tissues like the liver and muscle, SIRT1 activated by means of caloric restriction, activates gluconeogenic genes.

Hypothalamic SIRT1 overexpressed in the ARC and PNV nuclei induce weight gain and obesity.

Hypothalamic SIRT1 overexpressed in the DMH and LH nuclei suppresses the ARC/PNV nuclei and promotes youthful physiology and longevity.

Conclusions

SIRT1 has been the center of an intense debate since the first moment it was identified and related to a possible life span extension and longevity.

It is clear that the reason for the dispute lies in the different techniques and approaches used to analyze and characterize the role of SIRT in longevity.

Hypothalamic SIRT1 in the DMH and LH nuclei of the hypothalamus appears to be the key to longevity.

References

Amat R, Planavila A, Chen SL, Iglesias R, Giralt M, Villarroya F. 2009. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD. J Biol Chemistry [Internet; cited 2013 Oct 17] Doi:10.1074/jbc.M109.022749 [284(33): 21872–21880] Available in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755911/

Caito S, Rajendrasozhan S, Cook S, Chung S, Yao H, Friedman AE, Brookes PS, Rahman I. 2010. SIRT1 is a redox-sensitive deacetylase that is post-transcriptionally modified by oxidants and carbonyl stress. FASEB J. 24(9): 3145-3159

Ҫakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA. 2009. Hypothalamic SIRT1 Regulates Food Intake in a Rodent Model System. PLoSONE. 4(12): e8322. doi: 10.1371/journal.pone.0008322.

Gurd BJ, Perry CGR, Heigenhauser GJF, Spriet LL, Bonen A. 2010. High-intensity interval trining increases SIRT1 activity in human skeletal muscle. Appl. Physiol. Nutr. Metab. 35: 350-357

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Kelly, G. 2010. A Review of the Sirtuin System, its Clinical Implications, and the Potential Role of Dietary Activators like Resveratrol: Part 1. AMR. 15(3): 245-263

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Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA, Imai S. 2013. Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metabolism. 18: 416-430.

Singh BK, Sinha RA, Zhou J, Xie SY, You SH, Gauthier K, Yen PM. 2013. FOX01-Deacetylation regulates Thyroid Hormone Induced Transcription of Key Hepatic Gluconeogenic Genes. J Biol Chemistry. [Internet; cited 2013 Nov 7] Doi: 10.1074/jbc.M113.504845 [288: 30365-30372] Available in: http://www.jbc.org/content/early/2013/08/30/jbc.M113.504845.full.pdf+html