Table 1.

Summary of the effects of known mammalian SIRTs, their localization, activity and main functions.

SIRT	Cell Location	Tissue Expression	Enzyme Activity	Major Functions	Implication in AD Pathophysiology and/or Therapy (In Vitro/In Vivo Animal Model for AD)
SIRT1	Nuclear Cytosolic	Brain, retina, musculo-skeletal tissue, adipose tissue, heart, liver kidney, testis, uterus, blood vessels	Deacetylase, deacylase	DNA repair, Chromatin regulation, Cell cycle, Cell, survival, Neuroprotection, Metabolism, Cardio-vascular protection, Inflammation Ageing.	SIRT1 is involved in the regulation of APP processing and the clearance of Aβ and its activation provides neuroprotection [90]. SIRT1 modulates tau phosphorylation by deacetylating tau protein and influencing the activity of kinases and phosphatases, such as PP2A activation leading to a decrease in tau phosphorylation [91]. SIRT1 regulates neuroinflammation via NF-κB [52,92], highly expressed in AD. SIRT1 promotes mitochondrial biogenesis via activation of mitochondrial PGC-1α gene expression [93], which may lead to a reduction in oxidative stress reported in AD.
SIRT2	Nuclear Cytosolic	Brain, musculo-skeletal tissue, adipose tissue, heart, liver kidney, blood vessels	Deacetylase, deacylase	Cell control, Neuroinflammation, Myelination, Oxidation, Metabolism.	Activation of SIRT2 promotes tau phosphorylation via ERK activation. SIRT2 inhibition leads to reduced tau pathology and an increase in Aβ clearance in AD [94,95,96].
SIRT3	Mitochondrial Nuclear Cytosolic	Brain, musculo-skeletal tissue, adipose tissue (particularly brown), heart, liver kidney, oocytes blood vessels	Deacetylase, Decrotonylase	Cell, survival, Neuroprotection, Metabolism, Mitochondrial homeostasis, Inflammation, Oxidation (including FA), Thermogenesis, Ageing.	SIRT3 activation promotes the increase in neuronal survival and decrease apoptotic gene expression, reduces oxidative stress, regulates mitochondrial homeostasis (including increased bioenergetics), decreases neuroinflammation present in AD [97,98,99]
SIRT4	Mitochondrial	Brain, heart, kidney, liver, blood vessels, pancreatic β-cells	Deacetylase, ADP-ribosyltransferase, Lipoamidase, Deacylase	DNA repair, cell survival, Neurodegeneration, Cardio-vascular protection, Oxidation, Metabolism.	SIRT4 activation decrease oxidative stress and increase energy production in mitochondria [81]. SIRT4 modulates apoptosis via the mTOR pathway in AD [100].
SIRT5	Mitochondrial Nuclear Cytosolic	Brain, heart, kidney, liver, blood vessels, testis, thymus, musculoskeletal tissue	Deacetylase, Desuccinylase, Demalonylase, Deglutarylase	Oxidation (including FA)	SIRT5 regulates mitochondrial enzymes (via post-translational modifications), energy metabolism and response to oxidative sterss (via SOD2) [101]. Activation of SIRT5 represses Aβ production in AD by targeting autophagy [102]
SIRT6	Nuclear Cytosolic	Brain, retina, heart, kidney, liver, blood vessels, musculoskeletal tissue, thymus, testis, ovary	Deacetylase, Demyristoylase, ADP-ribosyl-transferase, Deacylase	DNA repair, Metabolism, Cardio-vascular protection, Inflammation Ageing.	Activation of SIRT6 is provides DNA stability and promotes DNA repair, leading to neuronal protection in AD [103]. Activation of SIRT6 reduces tau phosphorylation by deacetylating of tau protein [104].
SIRT7	Nucleolar Nuclear	Brain, heart, kidney, liver, blood cells, musculoskeletal tissue, spleen, testis	Deacetylase, Desuccinylase	Metabolism, Thermogenesis, Ageing.	SIRT7 deficiency protects against Aβ-induced apoptosis via regulation of ROS in cells [105].