Mechanism of action of Rapamycin for prolonging the age?

1. Authors_ 

   Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) , Professor and Head of Pathology, Convener & incharge DCP&DLT  School of Tropical Medicine, Kolkata ,108 CR Avenue Kol-73;W.B; Ex Professor of Pathology&  Ex in  charge of Histopathology Unit, in charge Blood Bank &VCCTC, in charge of Cytogenetics. Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India; Miss Upasana Bhattacharya of Mahamyatala, Garia kol-84 Daughter of Prof. Pranab Kr. Bhattacharya; Mr. Rupak Bhattacharya BSc(Cal);MSc(JU); Mr Ritwik Bhattacharya  B.com(cal) ; Miss Rupsa Bhattacharya; Mr Soumayak Bhattacharya - all of   residence 7/51 purbapalli, Sodepur Dist 24 parganas(North) Kol-110, West Bengal, India; ; 

   
   

   
   

   Rapamycin was originally isolated from a bacterium found on Rapa Nui, the indigenous name for Easter Island. Rapamycin (Rapamune®, Wyeth Ayerst, sirolimus) is a specific inhibitor of the target of rapamycin (TOR). Rapamycin is also a powerful suppressor of the human immune system, as cell anti proliferating drug, so commonly given to organ[Kidney] transplant patients[6mg as soon as after transplant, then 2mg daily for 2-3months as maintenance dose] to help to prevent the rejection of transplanted organs, used with cardiac drug eluting stents[to prevent proliferation of endothelial cells after stent] and may be used as a cancer adjuvant therapy, and also in autosomal dominent polycystic kidney disease. The drug is very costly approximately costs Rs12000/=, in Indian currency a month. Orthologue (mTOR), is also referred to as FKBP12-rapamycin associated protein (FRAP), rapamycin and FKBP12 target (RAFT), rapamycin target (RAPT), or sirolimus effector protein (SEP). mTOR lies downstream of IGF and has been implicated in several pathways that contribute to tumorigenesis, such as translation initiation and cap-dependent translation. The protein kinase TOR genes (TOR1 and TOR2) were first identified in the early 1990s in a screen for rapamycin-resistant yeast mutants¹ . Rapamycin forms a complex with the immunophilin FK506 binding protein-12 (FKBP12), which binds to the FKBP12-rapamycin binding (FRB) domain of mTOR and inhibits its kinase activity. Rapamycin thus can inhibit the growth of a broad spectrum of cancers including rhabdomyosarcoma, neuroblastoma, glioblastoma, small cell lung carcinoma, osteosarcoma, pancreatic cancer, leukaemia, B-cell lymphoma, and breast and colon cancer-derived cells²The rapamycin analogues, CCI-779 (Wyeth-Ayerst, PA, USA), RAD001 (Novartis, Switzerland), and AP23573 (Ariad Pharmaceuticals, MA, USA) have shown promise in clinical trials³ .mTOR functions by integrating extracellular signals (growth factors and hormones), with amino-acid availability and intracellular energy status to control translation rates and additional metabolic processes⁴ .mTOR enhances translation initiation in part by phosphorylating two major targets, the eIF4E binding proteins (4E-BPs) and the ribosomal protein S6 kinases (S6K1 and S6K2) that cooperate to regulate translation initiation rates.⁵ In Peutz Jeghers syndrome, Tuberous Sclerosis, and other diseases where PTEN is inactivated, the use of rapamycin as a clinical means to reverse the effect of elevated mTOR activity is an attractive option⁵. These diseases are distinct from other hamartoma-associated disorders (such as VHL syndrome) since they have an established molecular link to mTOR. Earlier studies demonstrated that PTEN-inactivated tumour cells exhibit enhanced sensitivity to the rapamycin analog CCI-779⁶ More recently, several studies have shown that rapamycin treatment, in combination with other chemotherapeutic drugs, can lead to enhanced selective killing of cancer cells. In particular, the protein tyrosine kinase (PTK) inhibitor, Imatinib (Gleevec, STI571) synergises with rapamycin to inhibit BCR/ABL transformed cells⁷ . The effect of rapamycin may be enhanced as a result of Imatinib-induced Akt/mTOR signaling, a complication that is thought to lead to Imatinib resistance. Rapamycin can also synergise with paclitaxel, carboplatin, and vinorelbine to induce apoptosis in breast cancer cells⁸ Cisplatin-induced apoptosis of A549 lung cancer cells is also significantly enhanced when combined with RAD001⁹ . This could be in part due to reduced translation of p53-activated p21 mRNA in A549 and MCF7 cells treated with RAD001, thereby allowing the dosage of cisplatin to be reduced Also, the use of theEGFR/VEGFR inhibitor, AEE788, in combination with RAD001 greatly decreased tumour growth in glioma xenografts (Goudar et al, 2005). Furthermore, targeting the glycolytic pathway in combination with mTOR inhibition may also be useful in cases where DNA-damaging agents are less efficient in inhibiting growth and promoting apoptosis of cancer cells¹⁰ .

   Aging is the progressive, universal decline first in functional reserve and then in function that occurs in organisms over time. Aging is heterogeneous. It varies widely in different individuals and in different organs within a particular individual. Aging is not a disease; however, the risk of developing disease is increased, often dramatically, as a function of age. The biochemical composition of tissues changes with age; physiologic capacity decreases, the ability to maintain homeostasis in adapting to stressors declines, and vulnerability to disease processes increases with age. After maturation, mortality rate increases exponentially with age

   Some Theories of Aging¹¹

   Hypothesis How It May Work

   Genetic Aging is a genetic program activated in post-reproductive life when an individual’s evolutionary mission is accomplished

   Oxidative stressAccumulation of oxidative damage to DNA, proteins, and lipids interferes with normal function and produces a decrease in stress responses

   Mitochondrial dysfunction A common deletion in mitochondrial DNA with age compromises function and alters cell metabolic processes and adaptability to environmental change

   Hormonal changes The decline and loss of circadian rhythm in secretion of some hormones produces a functional hormone deficiency state

   Telomere shortening Aging is related to a decline in the ability of cells to replicate

   Defective host defenses The failure of the immune system to respond to infectious agents and the over activity of natural immunity create vulnerability to environmental stresses

   Accumulation of senescent cells Renewing tissues become dysfunctional through loss of ability to renew

   So it is not well understood how rapamycin actually prolongs life affecting the ageing process and how its connected to calorie restriction and ageing? Through sirolimus effectors protein (SEP)? Then ageing process can be slowed by a drug therapy starting at an advanced age? should healthy individuals over age 50 consider taking rapamycin to slow his/her ageing?. However it is too costly therapy then. Moreover there are many adverse drug reactions of rapamycin like opportunistic infections, lynmhocele lymphoedema, sepsis, tachycardia hepatotoxicity susceptibilities to lymhoma and other malignancies, exfoliative dermatities azospermia to name a few. Mice are known to live longer if fed a calorie-restricted diet that is close to starvation levels, but this would be very difficult for a person to maintain. what should be the dose?

   References

   ¹ Heitman J, Movva NR, Hall MN Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science1991; 253: 905–909 |

   ²Huang S, Houghton PJ Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002;3: 295–304 |

   ³ Panwalkar A, Verstovsek S, Giles FJ Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer2004; 100: 657–666 |

   ⁴ Hay N, Sonenberg N Upstream and downstream of mTOR. Genes Dev2004; 18: 1926–1945

   ⁵E Petroulakis, Y Mamane, O Le Bacquer, D Shahbazian and N Sonenberg mTOR signaling: implications for cancer and anticancer therapy British Journal of Cancer 2006; 94, 195–199. doi:10.1038/sj.bjc.6602902 http://www.bjcancer.com/Published online 13 December 2005

   ⁶ Guertin DA, Sabatini DM An expanding role for mTOR in cancer. Trends Mol Med 2005;11: 353–361

   ⁷ Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG, Neel BG Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA2004; 101: 3130–3135

   ⁸ Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res2004; 10: 7031–7042

   ⁹ Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’Reilly T, Natt F, Hall J, Lane HA, Thomas G The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005;120: 747–759

   ¹⁰ Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P () Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia2005; 19: 2153–2158

   ¹¹ Lisa B. Caruso; Aging; Chapter 9. Geriatric Medicine page at Harrison’s Internal Medicine17th ed edited by

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   This article was published in most prestigious Journal of World " Nature Journal News Blogs" on 7th august 2009 as comment to article  Of mice, men and rapamycin
   

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