Prevention of cancer by inhibiting aging

Blagosklonny, Mikhail V.

doi:10.4161/cbt.7.10.6663

Cited by 105 publications

(93 citation statements)

References 87 publications

(112 reference statements)

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“…As cancer is an aging‐related disease and the pathways related to longevity represent potential targets for anticancer therapies,28 we investigated the role of class I α‐1,2‐mannosidases in liver cancer.…”

Section: Resultsmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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Section: Resultsmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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“…Our results alongside with recent findings of mTOR signaling pathway involvement in regulation of aging 44,46 and evidence of significant life span extension of mammals with rapamycin and calorie restriction 10,12,18,39 suggest that mimetic of calorie restriction, anti-diabetic biguanide metformin may be rapidly contemplated for pharmacological intervention at a population level taking in consideration sex and age-associated peculiarities of this drug's effect. …”

Section: Discussionmentioning

confidence: 78%

“…[9][10][11][12] It was suggested to use biguanide antidiabetic drugs (phenformin, buformin and metformin) as a potential anti-aging treatment. [13][14][15][16][17][18][19] The antidiabetic drugs were observed to reduce hyperglycemia and produce the following effects: improved glucose utilization; reduced free fatty acid utilization, gluconeogenesis, blood serum lipids, insulin and IGF-1, and reduced body weight both in humans and experimental animals. [13][14][15][16][17][18][19] The use of phenformin in humans has been limited the last 2 decades because of a potential association with lactic acidosis.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15][16][17][18][19] The antidiabetic drugs were observed to reduce hyperglycemia and produce the following effects: improved glucose utilization; reduced free fatty acid utilization, gluconeogenesis, blood serum lipids, insulin and IGF-1, and reduced body weight both in humans and experimental animals. [13][14][15][16][17][18][19] The use of phenformin in humans has been limited the last 2 decades because of a potential association with lactic acidosis. Widely used antidiabetic biguanide, metformin (dimethylbiguanide) do not increase risk for lactic acidosis or for increased lactate levels in type 2 diabetes, 20 but has some adverse effects, including renal insufficiency in some patients, 21 vitamin B 12 deficiency, 22 and gastrointestinal disturbances.…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

et al. 2014

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The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone -IGF-1 -insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (C20%, P < 0.05) and slightly increased the maximum life span (C3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (¡9.1% and ¡13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.

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“…1,[21][22][23][24] Therefore, rapalogs such as rapamycin are considered for both prevention of cancer and extension of healthy life span in humans. [25][26][27][28][29][30][31] There is a concern that potential side effects may limit rapamycin use as anti-aging drug. This concern is exaggerated.…”

Section: Introductionmentioning

confidence: 99%

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

Popovich

Anisimov

Zabezhinski

et al. 2014

Cancer Biology & Therapy

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Prevention of cancer by inhibiting aging

Cited by 105 publications

References 87 publications

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

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