Mechanism of aging and treatment option

Aging long considered to be solely the result of wear and tear is in fact regulated by specific genetic pathways. Simple changes in the environment (e.g. dietary restriction) can drastically extend lifespan, suggesting that several of these genetic pathways control longevity in response to changes in the surroundings. Hormonal signaling insulin and insulin like signaling Increase in lifespan C. elegans. Mutation DAF-2,IRS Chico Drosophila- Overexpression of foxo The insulin receptor mediates its effects via the PI3K-AKT/SGK signaling pathway, which culminates in the negative regulation of Forkhead transcription factor FOXO/DAF- 16 . Insulin signaling regulates aging in a conserved manner, from worms to mammals. Growth hormone signaling Increase in lifespan Mice- mutation in he pituitary transcription factors PIT1 (POU1F1) and PROP1 a null mutation in the GH receptor (GHR/) KLOTHO Increase in lifespan Mice- overexpression of klotho klotho has been found to repress insulin/IGF1 signaling and to regulate phosphate and calcium homeostasis by affecting fibroblast growth factor 23 (FGF23)and the Na+/K+-ATPase AC5 Increase in lifespan Mice lacking type 5 adenylyl cyclase (AC5)increased Raf-MEK- ERK signaling TGF TGF and the insulin pathways might regulate lifespan by acting on similar subsets of genes. Increase in lifespan Worms- mutations in TGF (daf-7) or in the TGF receptors DAF-1 (TGFR1) and DAF-4 (TGFR2) . DAF-3, together with its co-activator DAF-5, upregulates genes involved in cell cycle arrest and apoptosis, a large number of which are also regulated by the FOXO transcription factor DAF-16 . Steroid signaling Worms, the loss-of-function mutation of a cytochrome P450 (daf-9), a predicted steroidogenic hydroxylase, extends lifespan in a manner that is dependent on DAF-12

Nutrient sensing and signaling

DR without the malnutrition Sirtuin deacetylases - Sirtuin family of NAD-dependent protein deacetylases Increase in lifespan Worm- An increased number of copies of sir-2.1 Mice - Sirt6/ display signs of accelerated aging Polymorphism in the human SIRT3 gene has been correlated with increased survival in centenarians Sirtuin proteins are one of the targets of the polyphenol compound resveratrol, which extends lifespan of invertebrates and obese mice.
The Sirtuin pathway intersects with the insulin/IGF1 pathway

AMPK Increase in lifespan worms -AMPK overexpression

AMPK activation in mammalian cells is known to result in the inhibition of target of rapamycin (TOR), a protein kinase that regulates protein translation (Inoki et al., 2003); so, part of the effects of AMPK on longevity could also be mediated by TOR AMPK acts in part via FOXO transcription factors . AMP-activated protein kinase (AMPK) is an energy sensor that is activated in response to low energy levels. Compounds that activate AMPK have been proposed to act as DR mimetics AMPK is also activated by resveratrol TOR and translation signaling Increase lifespan Worms - Mutation of TOR - Knocking down three translational regulators, eIF4G, eIF4E and eIF2B homologs, or p70S6K (RSKS-1) -mutation of raptor (DAF-15), a protein that forms a regulatory complex with TOR. TOR regulates translation through activation of p70S6K and inhibition of the translation repressor eIF4EBP. FOXA/PHA-4 FOXA/PHA-4, another transcription factor of the Forkhead family, plays a central role in the extension of longevity induced by DR in worms - by upregulating a set of superoxide dismutase genes NRF1/SKN-1 DR-induced longevity is also mediated by a member of the family of bZIP transcription factors called SKN-1 in worms (NRF1 in mammals). Decrease lifespan Worm- A mutation in skn-1 by increasing the respiration rate

Mitochondria and ROS signaling

Mitochondria have been proposed to act as central organelles in the regulation of organismal aging (Wallace, 2005), because they control cellular energy levels, reactive oxygen species (ROS) production/detoxification and apoptosis, all of which are crucially important in determining lifespan. ETC components, Clk-1 and p66shc Increase lifespan Worm - Loss-of-function mutations in clk- 1, which encodes a protein required for the biosynthesis of ubiquinone (coenzyme Q), an essential cofactor in the ETC -Mutation of the iron sulfur protein (ISP-1) of the mitochondrial complex III Reducing the energy production and/or reducing the production of ROS associated with electron transfer is crucial for lifespan extension. Mice - Deletion of the gene encoding p66shc Stress-induced protein kinases: JNK and MST-1 Worm - activation of JNK, a MAP kinase family member activated by oxidative stress, extends longevity -overexpression of JNK leads to a FOXO- dependent increase lifespan - The expression of another oxidative-stress- induced protein kinase (MST-1)

Genome surveillance pathways

Mutations in a number of DNA repair genes (XPD, ATM, WRN, BLM, TOP3B and POLG) cause premature aging. Telomere maintenance is also crucial for a normal lifespan. Telomere synthesis requires both telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). Mice lacking TERC (mTR/) display signs of accelerated aging

Tumor suppressors and antagonistic pleiotropy Tumor suppressors are likely to help promote longevity by preventing cancer. antagonistic pleiotropy theory of aging. For example, a mouse mutant that has constitutively activated p53 develops fewer tumors but also shows signs of rapid aging. Mice overexpressing p44, a truncated activating version of p53, also have shortened lifespans HGPS In HGPS fibroblasts found 2 forms of lamin A by analysing: Hutchinson-Gilford Progeria Syndrome mRNA by electrophoresis & protein by Western blotting (i) normal (ii) shorter form (splice variant) Abnormal form = progeria normal lamin A-component of the nuclear lamina which supports the nuclear membrane Synthesis of lamin A mRNA lamin A pre-lamin A protein post-translational modifications pre-lamin As C-terminal end cleaved Lamin A The mature lamin A is released Progerin mutation prevents this normal cleavage progerin remains anchored to the inner nuclear membrane & accumulates there. Can the key post-translational modification cysteine farnelysation which allows the binding to the inner nuclear membrane be blocked? In cultured cells farneslyl transferase inhibitors (FTase inhibitors) e.g.Tipofarnib (drug) can restore cells Problems: - many other proteins need to be farnesylated for their physiological function - drugs toxic side-effects - treatment has to be halted until toxicity disappears

Telomerase
4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase oestrogen receptor (TERTER) under the transcriptional control of the endogenous TERT promoter i.e. normally this gene is switched off - If give 4-hydroxytamoxifen it will switch on the synthesis of telomerase. + 4-OHT for 4 weeks telomere restoration p53 tissue apoptosis restored normal testes & spleen size restoration of fecundity survival some CNS effects Nutrient sensors TOR is one of the established nutrient sensors Drug rapamyin inhibits TOR in mice lifespan (even old ones) Rapamycin is already approved for immune suppression (may preclude its effectiveness in people for ageing!) Progerin Anti-progerin drug is licensed for HutchinsonsGuildford progeria In normal ageing, increase in aberrant Lamin A ? such a drug may help noraml aging people too