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Rejuvenating immunity: “anti-aging drug today” eight years later
Cocaine sunny day
Rejuvenating immunity: “anti-aging drug today” eight years later
Cocaine sunny day
Cocaine sunny day
Rejuvenating immunity: “anti-aging drug today” eight years later
Federal government websites often end in. The site is secure. Yet, this turning point was predicted a decade ago. But what will cause human death, when aging will be abolished? Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR Target of Rapamycin. TOR-centric model predicts that rapamycin and other rapalogs can be used in humans to treat aging and prevent diseases \\\\\\\\\[ 2 \\\\\\\\\]. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans \\\\\\\\\[ 2 , 3 \\\\\\\\\]. This theory was ridiculed by opponents and anonymous peer-reviewers. And this prediction has been fulfilled. The study that Evirolimus RAD , a rapamycin analog, improves immunity in aging humans \\\\\\\\\[ 5 \\\\\\\\\] made sensational headlines:. Finally, rapamycin will be most useful as an anti-aging drug to slow down senescence and to prevent diseases. In simple words, rapamycin rejuvenates the immunity. As recently reviewed, in proper doses, lifespan-extending agents including rapamycin posses certain immunostimulatory activities \\\\\\\\\[ 6 \\\\\\\\\]. By , many predictions of the TOR-centric model have been tested and confirmed \\\\\\\\\[ 7 \\\\\\\\\]. Until December , all gerontological papers on rapamycin stated that current rapalogs are just proof of principle and will not be used due to side effects. Even further, use of anti-aging drugs in our lifetime was called science fiction. For unclear reasons, scientists emphasized that rapamacin and other current rapalogs will not be used in aging humans due to imaginary side effects. For example, rapamycin increases lipolysis, thus imitating fasting \\\\\\\\\[ 3 \\\\\\\\\]. Rapamycin, as calorie-restriction-mimetic, can cause starvation-like symptoms in certain conditions. This benevolent rapamycin-induced state prevents complications of true type II diabetes \\\\\\\\\[ 9 , 10 \\\\\\\\\]. In certain strains of mice, rapamycin causes some symptoms of starvation-like insulin-resistance, erroneously viewed as real diabetes \\\\\\\\\[ 11 \\\\\\\\\]. These metabolic alterations are reversible \\\\\\\\\[ 12 , 13 \\\\\\\\\]. MTOR-centric model predicts that this reversible insulin resistance is benevolent and is associated with increased longevity because longevity is promoted not via increased insulin sensitivity, but instead via decreased mTOR pathway signaling \\\\\\\\\[ 9 \\\\\\\\\]. Initially, mTOR-centic model was ignored. As it was predicted in \\\\\\\\\[ 4 \\\\\\\\\], opponents indeed take mTOR-centric model for granted. This is the ultimate triumph of the TOR-centric hyperfunction theory of aging. Evolutionary theory predicts that growth-promoting pathways are antagonistically pleiotropic \\\\\\\\\[ 16 \\\\\\\\\]. In other words, growth-promoting signaling is essential during development and may be harmful later in life. In particular, the nutrient-sensing mTOR pathway is essential for growth and development. In adults, its excessive activity leads to pathology aging \\\\\\\\\[ 17 - 20 \\\\\\\\\]. Aging is an unintended, harmful continuation of developmental growth. It is a quasi-program not a program , a shadow of development. More on that was discussed previously \\\\\\\\\[ 16 , 21 - 27 \\\\\\\\\]. The work in model organisms revealed numerous genes whose inactivation extends life span \\\\\\\\\[ 3 , 28 - 57 \\\\\\\\\]. Some gerogenes encode the TOR pathway. Yet, is the TOR pathway central or just one of the numerous pathways? Independent work on cellular senescence answers this question. In it was proposed that activation of growth-promoting pathways should cause senescence, when the cell cycle is blocked \\\\\\\\\[ 58 \\\\\\\\\]. In fact, mTOR converts reversible cell cycle arrest to cellular senescence geroconversion \\\\\\\\\[ 59 - 61 \\\\\\\\\]. Rapamycin partially suppresses geroconversion \\\\\\\\\[ 62 - 76 \\\\\\\\\]. All gerogenic pathways converge on the mTOR pathway: upstream and downstream \\\\\\\\\[ 77 - 83 \\\\\\\\\]. Typically, oncogenes are gerogenes, whereas tumor suppressors are gerosuppressors \\\\\\\\\[ 59 , 84 - 87 \\\\\\\\\]. Gerogenes and gerosuppressors constitute the mTOR network. This network is identical to gerogenic pathways identified in model organisms \\\\\\\\\[ 3 \\\\\\\\\]. Completely independently, mTOR pathway was revealed in the studies of human diseases: Parkinson and Alzheimer, cancer and benign tumors, cardiac fibrosis and atherosclerosis, renal hypertrophy and diabetic complications \\\\\\\\\[ 19 , 88 - 97 \\\\\\\\\]. And while gerontologists thought that rapamycin causes cancer, numerous studies by nephrologists and transplantologists showed that rapamycin prevents cancer in humans \\\\\\\\\[ 86 , 98 - \\\\\\\\\]. Most studies were performed by scientists, working in narrow clinical fields \\\\\\\\\[ - \\\\\\\\\]. Only taken together, these studies illuminate the role of mTOR in all age-related diseases. These age-related diseases are direct causes of death in aging. No one dies from aging per se. This generalization, combined with discoveries in model organisms and cellular senescence, was taken a step further \\\\\\\\\[ 2 \\\\\\\\\]. Examples of systemic hyperfuctions include hypertension, hyper-insulinemia and organ hypertrophy. Currently, humans and animals in protected environment die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer \\\\\\\\\[ - \\\\\\\\\]. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important? Consider an analogy. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening as examples eventually would cause post-aging syndrome \\\\\\\\\[ 2 \\\\\\\\\]. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over years old and especially in animals treated with rapamycin and other anti-aging modalities. Inhibition of mTOR may extend life span, thus revealing post-aging syndrome. How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed. As discussed in , causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on. As also discussed, when people die from post-aging syndrome, then anti-oxidants may help, in theory of course \\\\\\\\\[ 2 \\\\\\\\\]. Within this rather grand conceptual framework, I may be seen as an old-timer who desperately tries to salvage a doomed theory by piling up epicycles. Perhaps so — time will tell. Time told unexpectedly fast. While gerontologists were studying free radicals and anti-oxidants, the TOR-centric hyperfunction theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use \\\\\\\\\[ , \\\\\\\\\]. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension \\\\\\\\\[ 27 , \\\\\\\\\]. Simultaneously, medical progress improves aging-tolerance \\\\\\\\\[ , \\\\\\\\\]. Aging tolerance is the ability to survive despite aging \\\\\\\\\[ \\\\\\\\\]. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis. Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome not aging. It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now. As a library, NLM provides access to scientific literature. Published online Mar Mikhail V. Blagosklonny 1. Correspondence to: Mikhail V. Blagosklonny, Email: gro. Received Feb 16; Accepted Mar This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Genetics of longevity The work in model organisms revealed numerous genes whose inactivation extends life span \\\\\\\\\[ 3 , 28 - 57 \\\\\\\\\]. Cellular senescence In it was proposed that activation of growth-promoting pathways should cause senescence, when the cell cycle is blocked \\\\\\\\\[ 58 \\\\\\\\\]. Diseases Completely independently, mTOR pathway was revealed in the studies of human diseases: Parkinson and Alzheimer, cancer and benign tumors, cardiac fibrosis and atherosclerosis, renal hypertrophy and diabetic complications \\\\\\\\\[ 19 , 88 - 97 \\\\\\\\\]. Rattan SIS. Anti-ageing strategies: prevention or therapy. EMBO Rep. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Disc Today. Sci Transl Med. Immunostimulatory activity of lifespan-extending agents. Aging Albany NY ; 5 — Rapamycin and quasi-programmed aging: Four years later. Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging Albany NY ; 4 — TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging Albany NY ; 6 — Fang Y, Bartke A. Prolonged rapamycin treatment led to beneficial metabolic switch. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. Lamming DW. Diminished mTOR signaling: a common mode of action for endocrine longevity factors. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Validation of anti-aging drugs by treating age-related diseases. Aging Albany NY ; 1 — Prospective treatment of age-related diseases by slowing down aging. Am J Pathol. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging Albany NY ; 2 — Big mice die young but large animals live longer. MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. Aging is not programmed: Genetic pseudo-program is a shadow of developmental growth. Increasing healthy lifespan by suppressing aging in our lifetime: Preliminary proposal. Berman JR, Kenyon C. Germ-Cell Loss Extends C. Kenyon C. The plasticity of aging: insights from long-lived mutants. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF Dev Biol. Genetics: influence of TOR kinase on lifespan in C. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Cell Metab. Rejuvenation Res. Bjedov I, Partridge L. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans. Katewa SD, Kapahi P. Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. The TOR pathway comes of age. Biochim Biophys Acta. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS One. Cell Rep. Dysregulation of the mTOR pathway in pdeficient mice. Cancer Biol Ther. Remarkable longevity and stress resistance of nematode PI3K-null mutants. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. Alternative Perspectives on Aging in C. Antioxid Redox Signal. Gems D, Partridge L. Annu Rev Physiol. Cell senescence and hypermitogenic arrest. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Geroconversion: irreversible step to cellular senescence. Geriatric muscle stem cells switch reversible quiescence into senescence. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Rapamycin decelerates cellular senescence. The choice between pinduced senescence and quiescence is determined in part by the mTOR pathway. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. S6K in geroconversion. Suppression of replicative senescence by rapamycin in rodent embryonic cells. Pseudo-DNA damage response in senescent cells. Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Cho S, Hwang ES. Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells. Serrano M. Dissecting the role of mTOR complexes in cellular senescence. Dulic V. Senescence regulation by mTOR. Methods Mol Biol. Cell Stem Cell. Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence. Paradoxical suppression of cellular senescence by p Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells. MEK drives cyclin D1 hyperelevation during geroconversion. Cell Deth Diff. Berberine suppresses gero-conversion from cell cycle arrest to senescence. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Molecular damage in cancer: an argument for mTOR-driven aging. Aging Albany NY ; 3 — Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression? Rapalogs in cancer prevention: Anti-aging or anticancer? Selective anti-cancer agents as anti-aging drugs. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol. Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Nat Genet. Tee AR, Blenis J. Semin Cell Dev Biol. The expanding TOR signaling network. Curr Opin Cell Biol. TOR signaling in growth and metabolism. Curr Opin Genet Dev. Targeting mammalian target of rapamycin mTOR for health and diseases. Zheng XF. Chemoprevention of age-related macular regeneration AMD with rapamycin. J Am Soc Nephrol. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. Prevention of cancer by inhibiting aging. Immunosuppressants in cancer prevention and therapy. Paoletti E, Cannella G. Regression of left ventricular hypertrophy in kidney transplant recipients: the potential role for inhibition of mammalian target of rapamycin. Transplant Proc. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. Clin Breast Cancer. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Rapamycin fed late in life extends lifespan in genetically heterogenous mice. Rapamycin extends maximal lifespan in cancer-prone mice. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Rapamycin slows aging in mice. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Anisimov VN. Multifaceted aging and rapamycin. Aging Albany NY ; 5 Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Rapamycin in preventive very low doses. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration. Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Donehower LA. Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency. Zimniak P. What is the proximal cause of aging? Front Genet. Koschei the immortal and anti-aging drugs. Cell Death Disease. How to save Medicare: the anti-aging remedy. Hormesis does not make sense except in the light of TOR-driven aging. Copy Download.
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Rejuvenating immunity: “anti-aging drug today” eight years later
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