Answering the ultimate question “What is the Proximal Cause of Aging?”

Blagosklonny, Mikhail V.

doi:10.18632/aging.100525

Cited by 170 publications

(193 citation statements)

References 154 publications

(147 reference statements)

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“…Also, mTOR drives geroconversion from cell cycle arrest to senescence [56][57][58][59] and is involved in organismal aging. 60,61 Genetic data suggest the metformin acts through a similar mechanism. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, 56,57 are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla.…”

Section: Resultsmentioning

confidence: 99%

Metformin: Do we finally have an anti-aging drug?

Anisimov¹

2013

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

Metformin: Do we finally have an anti-aging drug?

Anisimov¹

2013

Cell Cycle

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“…In fact, cellular hyperfunction may link cellular senescence to organismal aging and age-related diseases. 30,66 As rapamycin did not inhibit MEK, as evidenced by ERK phosphorylation, its effect on cyclin D1 levels was MEK independent. MTORC1 can increase cyclin D1 expression via inactivation of eukaryotic initiation factor 4E-binding protein 1.…”

Section: Discussionmentioning

confidence: 99%

MEK drives cyclin D1 hyperelevation during geroconversion

2013

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When the cell cycle becomes arrested, MTOR (mechanistic Target of Rapamycin) converts reversible arrest into senescence (geroconversion). Hyperexpression of cyclin D1 is a universal marker of senescence along with hypertrophy, beta-Gal staining and loss of replicative/regenerative potential (RP), namely, the ability to restart proliferation when the cell cycle is released. Inhibition of MTOR decelerates geroconversion, although only partially decreases cyclin D1. Here we show that in p21-and p16-induced senescence, inhibitors of mitogen-activated/extracellular signal-regulated kinase (MEK) (U0126, PD184352 and siRNA) completely prevented cyclin D1 accumulation, making it undetectable. We also used MEL10 cells in which MEK inhibitors do not inhibit MTOR. In such cells, U0126 by itself induced senescence that was remarkably cyclin D1 negative. In contrast, inhibition of cyclin-dependent kinase (CDK) 4/6 by PD0332991 caused cyclin D1-positive senescence in MEL10 cells. Both types of senescence were suppressed by rapamycin, converting it into reversible arrest. We confirmed that the inhibitor of CDK4/6 caused cyclin D1 positive senescence in normal RPE cells, whereas U0126 prevented cyclin D1 expression. Elimination of cyclin D1 by siRNA did not prevent other markers of senescence that are consistent with the lack of its effect on MTOR. Our data confirmed that a mere inhibition of the cell cycle was sufficient to cause senescence, providing MTOR was active, and inhibition of MEK partially inhibited MTOR in a cell-type-dependent manner. Second, hallmarks of senescence may be dissociated, and hyperelevated cyclin D1, a marker of hyperactivation of senescent cells, did not necessarily determine other markers of senescence. Third, inhibition of MEK was sufficient to eliminate cyclin D1, regardless of MTOR. In proliferating cells, MTOR (mechanistic Target of Rapamycin) stimulates cellular mass growth, whereas cyclins D and E initiate S-phase transition.1-4 Withdrawal of growth factors causes reversible cell-cycle arrest (quiescence) with low levels of cyclins and MTOR activity, reversible by re-addition of growth factors. In contrast, cell-cycle arrest in the presence of growth stimuli, which activate MTOR, leads to cellular senescence. 5,6 In other words, when the cell cycle is blocked, while growth-promoting pathways such as MTOR remain active, cells continue to grow in size and undergo senescence. A process of conversion from normal reversible arrest into senescence was named as gerogenic conversion (geroconversion).7 Cellular senescence is characterized by large flat morphology (hypertrophy), beta-Gal staining, very high levels of cyclins D1 and E, senescence-associated secretory phenotype and loss of replicative/regenerative potential (RP).7-12 Loss of RP means that cells cannot proliferate even when cell-cycle block is removed and cells re-enter the cell cycle.13,14 Rapamycin decreases hypertrophy and loss of RP, in a dose-dependent manner proportional to S6 dephosphorylation (a marker of MTORC1 activity). 15Other ...

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“…In fact, organismal aging is an increase of the probability of death. It is the sum of age-related diseases and disease-like conditions [102][103][104][105] Inhibition of mTOR by calorie restriction or rapamycin decelerates geroconversion, and increases health-and life span. In other words deceleration of cellular geroconversion slows down organismal aging.…”

Section: From Cell Culture To the Organismmentioning

confidence: 99%