Metformin extends maximum, average lifespan

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Hi All,

" It will be interesting to evaluate metformin efficiency on other, e. g.

cancer-resistant animals. "

Major excerpts from the available pdf of the paper, which shows very short life

expectancies and details that the metformin-treated mice had greatly increased

slopes of longevity curves, are:

Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich

IG,

Semenchenko AV.

Metformin decelerates aging and development of mammary tumors in her-2/neu

transgenic mice.

Bull Exp Biol Med. 2005 Jun;139(6):721-3. English, Russian.

PMID: 16224592

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16224592 & query_hl=31

Caloric restriction (CR) is the most effective method

for life span prolongation in laboratory animals [1,3,

11]. This diet is associated with a stable decrease in

the levels plasma glucose, insulin, and many other

hormones, which gave grounds to call this method

“pseudohypophysectomy”, because of its similar ef-fects.

On the basis of these data and observations indi-cating

that hyperglycemia and hyperinsulinemia are

destructive for the organism, it was hypothesized that

the geroprotective effect of CR was explained by this

mechanism [11]. However it is obvious that CR is

hardly a perspective method for prolongation of the

life span of humans.

Great recent attention was paid to the search for

CR mimetics [1,14]. Antidiabetic biguanides seem to

be the most promising in this respect. Drugs of this

group (fenformin, buformin, metformin), along with

hypoglycemic effect, improve glucose utilization in

tissues, reduce utilization of fatty acids as energy sub-strates,

suppress neoglucogenesis, lower blood chole-sterol,

triglycerides, and insulin concentrations and

biosynthesis of cholesterol, and reduce body weight.

These effects of antidiabetic biguanides and their ca-pacity

to eliminate signs of metabolic immunosup-pression

prompted their use in oncological practice for

normalization of some metabolic disorders charac-teristic

of cancer patients [2,5,9,10,12]. It was previ-ously

shown that long-term treatment with fenformine

and buformine prolonged life span of nematodes [6],

mice, and rats and reduced the incidence of sponta-neous

tumors and tumors induced by chemical carci-nogens

or ionizing radiation [1,8,9,13]. Considering

the role of insulin in the pathogenesis of malignant

tumors these data are of particular importance [10,12].

Metformin (siofor) is now widely used in clinical prac-tice.

However, preliminary data on its geroprotective

activity just appeared [13].

We studied the effect of metformin on biological

age, life span, and development of tumors in female

mice carrying HER-2/neu breast cancer gene.

.... Starting from the age of 2 months the animals of one

group received 240 mg/kg metformin (siofor, Berlin-Chemie,

Menarini Group) with drinking water 5 days

a week until natural death.

.... RESULTS

Injection of metformin somewhat decreased fodder

consumption, but not drinking, and did not influence

the dynamics of weight gain. The mean life span (MLS)

of mice increased by 8% (p<0.05) under the effect of

the drug, in 10% long-living animals it was prolonged

by 13.1%, and the maximum life span was 1 month

longer than in the control (Table 1).

TABLE 1. Metformin Effect on the Life Span and Development of Mammary

Adenocarcinoma

in HER-2/neu Transgenic Mouse Females

==============

Parameter Metformin Control

==============

Number of mice 34 32

Life duration,days

Mean 264.0 ±3.5 285.0 ±5.2 +

Maximum 311 340

Mean life span of 10% long living mice,days 297.0 ±7.3 336.0 ±2.7 +

á ,day —1 *0.0762 0.0337 +

Number of mice of mammary tumors 34 (100%) 32 (100%)

Day of detection of the first tumor 135 128

Mean latent period of mammary tumor,days 174.0 ±2.4 187.0 ±3.5 +

Total number of tumors 290 263

Mean number of tumor per mouse in the group 8.50 ±0.25 8.20 ±0.23

Mean diameter of tumors,cm 1.790 ±0.055 1.590 ±0.056 +

Number of mice with metastases in the lung 24 (71%)23 (72%)

==============

*Constant a in Hompertz equation R=R 0 (exp)á t, where R 0 is mortality during

t= 0.

+ p<0.05 compared to the control.

The rate of popu-lational

aging in mice (constant á in Hompertz equation)

decreased 2.26 times (p<0.05) under the effect of met-formin,

while mouse survival curve shifted appreciably

to the right under the effect of metformin (Fig. 1, a).

The dynamics of mammary tumor development

was virtually the same in both groups until month 5

of life, after which a clear-cut deceleration of tumor

development was noted in the experimental group

(Fig. 1, . The incidence of mammary adenocarcino-mas

in mice carrying HER-2/neu gene was 100% in

both groups. The incidence, multiplicity, and inci-dence

of mammary tumor metastases in the lung also

virtually did not differ in the groups. The percentage

of mice with 4-6 tumors in the metformin group was

virtually the same as in the control group (8.9 and

9.3%, respectively), while the percentage of mice with

9 or 10 tumors decreased 2-fold under the effect of

metformin in comparison with the control (46.9 and

23.5%, respectively, p<0.05). The size of mammary

adenocarcinoma under the effect of the drug was also

somewhat lower (p<0.05).

Breast cancer is one of the most prevalent malig-nant

tumors and the leading cause of death from can-cer

in women [2]. Transgenic mice carrying HER-2/

neu gene belonging to the epidermal growth factor

tyrosine kinase receptors (EGFR) are characterized by

high incidence of mammary tumors and short life span

[1]. Our experiments demonstrate deceleration of aging

and development of breast tumors in this mouse strain

under the effect of metformin. Experiments on long-living

rats and mice resistant and sensitive to cancer

showed that other biguanides, e.g. fenformine and bu-formine,

were characterized by geroprotective and

anticarcinogenic effects [1,5,8,9]. The data on the anti-oxidant

effects of antidiabetic biguanides, their direct

effect on the mitochondria, and neuroprotective acti-vity

recommend biguanides for the prevention of neuro-degenerative

diseases [1-3]. Metformin modulated ac-tivities

of genes whose expression changed due to CR

[13]. Hence, we revealed a geroprotective effect of

metformin in mice and its inhibitory effect on the

development of tumors, caused by expression of HER-2/

neu oncogene. It will be interesting to evaluate met-formin

efficiency on other, e. g. cancer-resistant ani-mals.

Al Pater, PhD; email: old542000@...

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