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 TGFβ TGFβ and the insulin pathways might regulate lifespan by acting on similar subsets of genes. Increase in lifespan Worms- mutations in TGFβ (daf-7) or in the TGFβ receptors DAF-1 (TGFβR1) and DAF-4 (TGFβR2) . 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

Loss-of-function mutations in clk. TOR regulates translation through activation of p70S6K and inhibition of the translation repressor eIF4EBP.AMPK activation in mammalian cells is known to result in the inhibition of target of rapamycin (TOR). FOXA/PHA-4 FOXA/PHA-4.Deletion of the gene encoding p66shc Stress-induced protein kinases: JNK and MST-1 Worm . another transcription factor of the Forkhead family. Mice lacking TERC (mTR–/–) display signs of accelerated aging . 2005). reactive oxygen species (ROS) production/detoxification and apoptosis. WRN.dependent increase lifespan . Decrease lifespan Worm. which encodes a protein required for the biosynthesis of ubiquinone (coenzyme Q).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). plays a central role in the extension of longevity induced by DR in worms . 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 . so. part of the effects of AMPK on longevity could also be mediated by TOR AMPK acts in part via FOXO transcription factors . BLM. extends longevity -overexpression of JNK leads to a FOXO.1.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. or p70S6K (RSKS-1) -mutation of raptor (DAF-15). all of which are crucially important in determining lifespan. Mice . ATM. TOP3B and POLG) cause premature aging. 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. Telomere maintenance is also crucial for a normal lifespan. a protein kinase that regulates protein translation (Inoki et al. a MAP kinase family member activated by oxidative stress. 2003).The expression of another oxidative-stress. AMP-activated protein kinase (AMPK) is an energy sensor that is activated in response to low energy levels. Clk-1 and p66shc Increase lifespan Worm .. eIF4G.Mutation of TOR . because they control cellular energy levels. ETC components.activation of JNK. eIF4E and eIF2B homologs.Knocking down three translational regulators. a protein that forms a regulatory complex with TOR. Telomere synthesis requires both telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC).induced protein kinase (MST-1) Genome surveillance pathways Mutations in a number of DNA repair genes (XPD.

many other proteins need to be farnesylated for their physiological function . Mice overexpressing p44. For example. a mouse mutant that has constitutively activated p53 develops fewer tumors but also shows signs of rapid aging.drugs → toxic side-effects . increase in aberrant Lamin A ? such a drug may help noraml aging people too .Tipofarnib (drug) can restore cells Problems: .Tumor suppressors and antagonistic pleiotropy Tumor suppressors are likely to help promote longevity by preventing cancer. normally this gene is switched off .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. 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. + 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 Hutchinsons–Guildford progeria In normal ageing.If give 4-hydroxytamoxifen it will switch on the synthesis of telomerase.g. 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 A’s 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. a truncated activating version of p53.e. ‘antagonistic pleiotropy’ theory of aging.