Volume 3, Issue 11

Intermittent supplementation with rapamycin as a dietary restriction mimetic

Valter D Longo, Luigi Fontana,

https://doi.org/10.18632/aging.100401 pp 1039—1040

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Longo VD, Fontana L, . Intermittent supplementation with rapamycin as a dietary restriction mimetic. . 3:1039-1040. https://doi.org/10.18632/aging.100401

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Chronological lifespan in stationary culture: from yeast to human cells

Zoya N. Demidenko,

https://doi.org/10.18632/aging.100406 pp 1041—1042

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Rapamycin: Killing two birds with one stone

Amit Khanna, Pankaj Kapahi,

https://doi.org/10.18632/aging.100405 pp 1043—1044

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SkQ1 treatment and food restriction — two ways to retard an aging program of organisms

Vladimir P. Skulachev,

https://doi.org/10.18632/aging.100410 pp 1045—1050

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Skulachev VP, . SkQ1 treatment and food restriction — two ways to retard an aging program of organisms. . 3:1045-1050. https://doi.org/10.18632/aging.100410

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                TY  - JOUR
                AU  - Skulachev, Vladimir P. 
                TI  - SkQ1 treatment and food restriction — two ways to retard an aging program of organisms
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100410
                DO  - 10.18632/aging.100410
                SP  - 1045
                EP  - 1050
                PY  - 
                AB  - Effects of the mitochondria-targeted antioxidant SkQ1 and food restriction are compared. In both cases there is a remarkable increase in the median lifespan of organisms belonging to many different taxonomic ranks. Essentially, both SkQ1 treatment and restriction in food intake retard development of numerous adverse traits of senescence. This relationship could be predicted assuming that SkQ1 and food restriction inhibit the execution of an aging program. It is hypothesized that food restriction is perceived by organisms as a signal of starvation, which can be catastrophic for the population. Under these conditions, the organism switches off an aging program that is favorable for evolvability of the species but counterproductive for the individual. Unfortunately, food restriction is accompanied by some other effects, e.g., constant anxiety and attempts to scan as large a space as possible looking for food. Such side effects seem to be absent in the case of inhibition of the aging program by SkQ1.
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Hormesis does not make sense except in the light of TOR-driven aging

Mikhail V. Blagosklonny,

https://doi.org/10.18632/aging.100411 pp 1051—1062

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Blagosklonny MV, . Hormesis does not make sense except in the light of TOR-driven aging. . 3:1051-1062. https://doi.org/10.18632/aging.100411

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                TY  - JOUR
                AU  - Blagosklonny, Mikhail V. 
                TI  - Hormesis does not make sense except in the light of TOR-driven aging
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100411
                DO  - 10.18632/aging.100411
                SP  - 1051
                EP  - 1062
                PY  - 
                AB  - Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. “Hormesis A” inhibits the TOR pathway. “Hormesis B” increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.
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Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer

Javier A. Menendez, Sílvia Cufí, Cristina Oliveras-Ferraros, Begoña Martin-Castillo, Jorge Joven, Luciano Vellon, Alejandro Vazquez-Martin,

https://doi.org/10.18632/aging.100407 pp 1063—1077

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Menendez JA, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Vellon L, Vazquez-Martin A, . Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer. . 3:1063-1077. https://doi.org/10.18632/aging.100407

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Provider: 
                TY  - JOUR
                AU  - Menendez, Javier A. 
                AU  - Cufí, Sílvia 
                AU  - Oliveras-Ferraros, Cristina 
                AU  - Martin-Castillo, Begoña 
                AU  - Joven, Jorge 
                AU  - Vellon, Luciano 
                AU  - Vazquez-Martin, Alejandro 
                TI  - Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100407
                DO  - 10.18632/aging.100407
                SP  - 1063
                EP  - 1077
                PY  - 
                AB  - By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the ability to initiate tumors. As life-long or late-life removal of senescent cells has been shown to prevent or delay the onset or progression of age-related disorders, the tissue sweeper function of metformin may inhibit the malignant/metastatic progression of pre-malignant/senescent tumor cells and increase the human lifespan.
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Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression

Olga V. Leontieva, Mikhail V. Blagosklonny,

https://doi.org/10.18632/aging.100402 pp 1078—1091

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Leontieva OV, Blagosklonny MV, . Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. . 3:1078-1091. https://doi.org/10.18632/aging.100402

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                TY  - JOUR
                AU  - Leontieva, Olga V. 
                AU  - Blagosklonny, Mikhail V. 
                TI  - Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100402
                DO  - 10.18632/aging.100402
                SP  - 1078
                EP  - 1091
                PY  - 
                AB  - In yeast, chronological senescence (CS) is defined as loss of viability in stationary culture. Although its relevance to the organismal aging remained unclear, yeast CS was one of the most fruitful models in aging research. Here we described a mammalian replica of yeast CS: loss of viability of overgrown “yellow” cancer cell culture. In a density and time (chronological)-dependent manner, cell culture loses the ability to re-grow in fresh medium. Rapamycin dramatically decelerated CS. Loss of viability was caused by acidification of the medium by lactic acid (lactate). Rapamycin decreased production of lactate, making conditioned medium (CM) less deadly. Both deadly CM and lactate caused loss of viability in low cell density, not preventable by either rapamycin or additional glucose. Also, NAC, LY294002, U0126, GSK733, which all indirectly inhibit mTOR and have been shown to suppress the senescent phenotype in traditional models of mammalian cell senescence, also decreased lactate production and decelerated CS. We discuss that although CS does not mimic organismal aging, the same signal transduction pathways that drive CS also drive aging.
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Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus

Yuko Maejima, Daisuke Kohno, Yusaku Iwasaki, Toshihiko Yada,

https://doi.org/10.18632/aging.100400 pp 1092—1097

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Maejima Y, Kohno D, Iwasaki Y, Yada T, . Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus. . 3:1092-1097. https://doi.org/10.18632/aging.100400

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                TY  - JOUR
                AU  - Maejima, Yuko 
                AU  - Kohno, Daisuke 
                AU  - Iwasaki, Yusaku 
                AU  - Yada, Toshihiko 
                TI  - Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100400
                DO  - 10.18632/aging.100400
                SP  - 1092
                EP  - 1097
                PY  - 
                AB  - Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play an important role in feeding regulation. Plasma levels of ghrelin and insulin show reciprocal dynamics before and after meals. We hypothesized that ghrelin and insulin also exert reciprocal effects on ARC NPY neurons. Cytosolic Ca2+ concentration ([Ca2+]i) was measured by fura-2 microfluorometry in single neurons isolated from ARC of adult rats, followed by immunocytochemical identification of NPY neurons. Ghrelin at 10−10 M increased [Ca2+]i in isolated ARC neurons, and co-administration of insulin concentration-dependently suppressed the ghrelin-induced [Ca2+]i increases. Insulin at 10−16 M, 10−14 M, 10−12 M and 10−10 M counteracted ghrelin action in 26%, 41%, 61% and 53% of ghrelin-responsive neurons, respectively, showing a maximal effect at 10−12 M, the estimated postprandial concentration of insulin in the brain. The majority (&gt;70%) of the ghrelin-activated insulin-inhibited neurons were shown to contain NPY. Double-immunohistochemistry revealed that 85% of NPY neurons in ARC express insulin receptors. These data demonstrate that insulin directly interacts with ARC NPY neurons and counteracts ghrelin action. Our results suggest that postprandial increase in plasma insulin/ghrelin ratio and insulin inhibition of ghrelin action on ARC NPY neurons cooperate to effectively inhibit the neuron activity and terminate feeding.
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Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor

Lan Xiang, Yukiko Nakamura, Young-Mi Lim, Yasutoyo Yamasaki, Yumi Kurokawa-Nose, Wakako Maruyama, Toshihiko Osawa, Akira Matsuura, Noboru Motoyama, Leo Tsuda,

https://doi.org/10.18632/aging.100396 pp 1098—1109

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Xiang L, Nakamura Y, Lim Y, Yamasaki Y, Kurokawa-Nose Y, Maruyama W, Osawa T, Matsuura A, Motoyama N, Tsuda L, . Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor. . 3:1098-1109. https://doi.org/10.18632/aging.100396

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                TY  - JOUR
                AU  - Xiang, Lan 
                AU  - Nakamura, Yukiko 
                AU  - Lim, Young-Mi 
                AU  - Yamasaki, Yasutoyo 
                AU  - Kurokawa-Nose, Yumi 
                AU  - Maruyama, Wakako 
                AU  - Osawa, Toshihiko 
                AU  - Matsuura, Akira 
                AU  - Motoyama, Noboru 
                AU  - Tsuda, Leo 
                TI  - Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100396
                DO  - 10.18632/aging.100396
                SP  - 1098
                EP  - 1109
                PY  - 
                AB  - The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.
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Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents

Vladimir N. Anisimov, Maxim V. Egorov, Marina S. Krasilshchikova, Konstantin G. Lyamzaev, Vasily N. Manskikh, Mikhail P. Moshkin, Evgeny A. Novikov, Irina G. Popovich, Konstantin A. Rogovin, Irina G. Shabalina, Olga N. Shekarova, Maxim V. Skulachev, Tatiana V. Titova, Vladimir A. Vygodin, Mikhail Yu. Vyssokikh, Maria N. Yurova, Mark A. Zabezhinsky, Vladimir P. Skulachev,

https://doi.org/10.18632/aging.100404 pp 1110—1119

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Anisimov VN, Egorov MV, Krasilshchikova MS, Lyamzaev KG, Manskikh VN, Moshkin MP, Novikov EA, Popovich IG, Rogovin KA, Shabalina IG, Shekarova ON, Skulachev MV, Titova TV, et al, . Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents. . 3:1110-1119. https://doi.org/10.18632/aging.100404

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                TY  - JOUR
                AU  - Anisimov, Vladimir N. 
                AU  - Egorov, Maxim V. 
                AU  - Krasilshchikova, Marina S. 
                AU  - Lyamzaev, Konstantin G. 
                AU  - Manskikh, Vasily N. 
                AU  - Moshkin, Mikhail P. 
                AU  - Novikov, Evgeny A. 
                AU  - Popovich, Irina G. 
                AU  - Rogovin, Konstantin A. 
                AU  - Shabalina, Irina G. 
                AU  - Shekarova, Olga N. 
                AU  - Skulachev, Maxim V. 
                AU  - Titova, Tatiana V. 
                AU  - Vygodin, Vladimir A. 
                AU  - Vyssokikh, Mikhail Yu. 
                AU  - Yurova, Maria N. 
                AU  - Zabezhinsky, Mark A. 
                AU  - Skulachev, Vladimir P. 
                TI  - Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100404
                DO  - 10.18632/aging.100404
                SP  - 1110
                EP  - 1119
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Anisimov, Vladimir N. 
                AU  - Egorov, Maxim V. 
                AU  - Krasilshchikova, Marina S. 
                AU  - Lyamzaev, Konstantin G. 
                AU  - Manskikh, Vasily N. 
                AU  - Moshkin, Mikhail P. 
                AU  - Novikov, Evgeny A. 
                AU  - Popovich, Irina G. 
                AU  - Rogovin, Konstantin A. 
                AU  - Shabalina, Irina G. 
                AU  - Shekarova, Olga N. 
                AU  - Skulachev, Maxim V. 
                AU  - Titova, Tatiana V. 
                AU  - Vygodin, Vladimir A. 
                AU  - Vyssokikh, Mikhail Yu. 
                AU  - Yurova, Maria N. 
                AU  - Zabezhinsky, Mark A. 
                AU  - Skulachev, Vladimir P. 
                TI  - Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents
                JO  - 
                JA  - 
                VL  - 3
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100404
                DO  - 10.18632/aging.100404
                SP  - 1110
                EP  - 1119
                PY  - 
                AB  - The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.
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Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”)

Vladimir P. Skulachev,

https://doi.org/10.18632/aging.100403 pp 1120—1123

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Skulachev VP, . Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”). . 3:1120-1123. https://doi.org/10.18632/aging.100403

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Volume 3, Issue 11

Intermittent supplementation with rapamycin as a dietary restriction mimetic

Valter D Longo, Luigi Fontana,

Chronological lifespan in stationary culture: from yeast to human cells

Zoya N. Demidenko,

Rapamycin: Killing two birds with one stone

Amit Khanna, Pankaj Kapahi,

Hypotheses

SkQ1 treatment and food restriction — two ways to retard an aging program of organisms

Vladimir P. Skulachev,

Hormesis does not make sense except in the light of TOR-driven aging

Mikhail V. Blagosklonny,

Research Perspective

Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer

Javier A. Menendez, Sílvia Cufí, Cristina Oliveras-Ferraros, Begoña Martin-Castillo, Jorge Joven, Luciano Vellon, Alejandro Vazquez-Martin,

Research Papers

Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression

Olga V. Leontieva, Mikhail V. Blagosklonny,

Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus

Yuko Maejima, Daisuke Kohno, Yusaku Iwasaki, Toshihiko Yada,

Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor

Lan Xiang, Yukiko Nakamura, Young-Mi Lim, Yasutoyo Yamasaki, Yumi Kurokawa-Nose, Wakako Maruyama, Toshihiko Osawa, Akira Matsuura, Noboru Motoyama, Leo Tsuda,

Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents

Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”)

Vladimir P. Skulachev,

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