1. Settling the Debate
Hypothalamic Sirt1 as the Key to Longevity
Review Paper by:
Paola Caballero
RISE Program UPR-Cayey

2. 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
Acetyl
group
Guanine

3. 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.

4. Sirtuin 1
 Silent mating type
information-2
homolog (SIRT1)
 deacetylase protein
 Mainly found in:
nucleus and cytoplasm
 Silences histones
 Primary role: the
regulation of nonhistone substrates like
transcription factors.

6.  Regulate systemic and cellular adaptation in
response to various types of stresses.
Activation of
PGC-1a and FOX
proteins
Gene
Transcription
Mitochondrial
biogenesis
Stress
resistance
Gluconeogenesis

7. Factors that up-regulate
Sirt1

9. 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.

10. Aging
Oxidative Stress
Macromolecules
and cells are
oxidized
Many free
radicals
produced
Damage
biological
structures
Compromise
cellular
functions
Shorten lifespan
SIRT1 in Aging

11. 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.

12. 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.

13. 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.

14. Low
ATP
Improved
Metabolism and
disease
prevention
High
NAD+
Increased
Mitochondrial
activity and
biogenesis
High
SIRT1
Activity
Deacetylation of
PGC-1a, ERRa, FOX01
Sirtuins as
regulators of
metabolism

15. 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.

16. 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.

17. Hypothalamus
ARC/PNV
nuclei
SIRT1
Deacetylates
FOX01
Suppressed POMC, an
appetite regulator
Increase in AgRP,
which stimulates
appetite and food intake
Other
nuclei
SIRT1

18. 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

19. Hypothalamus
ARC/PNV
nuclei
SIRT1
DMH/LH
nuclei
SIRT1
Deacetylates
Nkx2-1
target gene
Ox2r
•sympathetic nervous system
ultimately skeletal muscle
function
•preserves quality of sleep
•increase of physical activity,
body temperature and oxygen
consumption.

20. 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.

21. 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.

22. References
 Amat R, Planavila A, Chen SL, Iglesias R, Giralt M, Villarroya F. 2009. SIRT1
controls the transcription of the peroxisome proliferator-activated receptorgamma 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 posttranscriptionally 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. PLoS
ONE. 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

23.  Houtkooper RH, Pirinen E, Auwerx J. 2012. Sirtuins as regulators of metabolism
and healthspan. Nature Reviews. Molec. Cell Biol. 13(4): 225-238
 Kelly, G. 2010. A Review of the Sirtuin System, its Clinical Implications, and the
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 Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA,
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Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metabolism. 18: 416430.
 Singh BK, Sinha RA, Zhou J, Xie SY, You SH, Gauthier K, Yen PM. 2013. FOX01-
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http://www.jbc.org/content/early/2013/08/30/jbc.M113.504845.full.pdf+html