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Cell Metabolism

Essay

Metformin as a Tool to Target Aging


Nir Barzilai,1,* Jill P. Crandall,1 Stephen B. Kritchevsky,2 and Mark A. Espeland2
1Institutefor Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
2Wake Forest Older Americans Independence Center and the Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem,
NC 27157, USA
*Correspondence: nir.barzilai@einstein.yu.edu
http://dx.doi.org/10.1016/j.cmet.2016.05.011

Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan
and health span in numerous models. Metformin, which has demonstrated protective effects against several
age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial
step in the development of increasingly effective next-generation drugs.

Introduction span and, most importantly, health span, (Harrison et al., 2014). Studies of rapamy-
Over the past decades, remarkable pro- the period of life during which an individual cin (an mTOR inhibitor) have established
gress has occurred in the science of is fully functional and free of chronic the most compelling evidence for tar-
aging in model organisms. Studies have illness. There is overwhelming evidence geting aging. When rapamycin is ad-
demonstrated that genetic pathways that single gene mutations in nutrient- ministered late in life, it extends lifespan
modulate healthy lifespan in diverse spe- sensing pathways, such as insulin/insu- (Harrison et al., 2009; Miller et al., 2011),
cies across great evolutionary distance lin-like growth factor (IGF) signaling slows aging in a dose-dependent manner,
and established that aging-related path- (Bartke et al., 2001) or the mechanistic shows differential effects by sex (Wilkin-
ways constitute a target for intervention target of rapamycin (mTOR) signaling son et al., 2012), and is synergistic with
(Barzilai et al., 2012; Longo et al., 2015). pathways, extend lifespan and health metformin.
Lifespan has been verifiably modulated span in invertebrates. More importantly,
by genetic, pharmacologic, and dietary these pathways have been evaluated in Metformin Modulates the Biology of
interventions in multiple model systems. mammalian models, in which health span Aging and Health Span in Model
With support from an R24 grant from and lifespan have been extended by ge- Organisms
the NIA (J. Kirkland, N.B., S. Austad), we netic manipulation or drugs (Johnson Metformin is a drug approved to treat dia-
gathered gerontologists with expertise in et al., 2013). This raises hope for new inter- betes but appears to target a number of
the biology of aging and in clinical geriat- ventions, including drugs that slow the aging-related mechanisms. Some mecha-
rics to discuss ways to target aging in hu- aging process and slow the appearance nisms are relevant to glucose metabolism,
mans. This effort resulted in the design of of age-related disease by modulating but with respect to aging these may not
the study Targeting Aging with Metfor- conserved pathways of aging, as further be the most important ones. Metformins
min (TAME). This trial has been under discussed and developed in recent re- multiple aging-relevant actions at the
reviews through several funding mecha- views (de Cabo et al., 2014; Fontana and cellular and organismal levels are de-
nisms and has received planning funding Partridge, 2015; Fontana et al., 2010). picted in Figure 1. Specifically for aging,
from the American Federation of Aging Interventions to Prolong Lifespan metformin leads to decreased insulin
Research. An intended consequence of Recognizing that aging can be targeted, levels, decreased IGF-1 signaling (Liu
this effort is to create a paradigm for eval- the NIH developed the NIA Interven- et al., 2011), inhibition of mTOR (Kickstein
uation of pharmacologic approaches to tions Testing Program (ITP). The ITP et al., 2010; Nair et al., 2014; Perez-Re-
delay aging. The randomized, controlled tests diets, drugs, or other interventions vuelta et al., 2014), inhibition of mitochon-
clinical trial we have proposed, if suc- to see if they prevent disease and drial complex 1 in the electron transport
cessful, could profoundly change the extend lifespan in genetically heteroge- chain and reduction of endogenous pro-
approach to aging and its diseases and neous (outbred) mice (http://www.nia.nih. duction of reactive oxygen species (ROS)
affect healthcare delivery and costs. If gov/research/dab/interventions-testing- (Batandier et al., 2006; Bridges et al.,
TAME demonstrates that metformin mod- program-itp). This program is conducted 2014; Zheng et al., 2012), activation
ulates aging and its diseases, beyond an at multiple centers in order to control for of AMP-activated kinase (AMPK) (Cho
isolated impact on diabetes, it would laboratory-specific environmental differ- et al., 2015; Duca et al., 2015; Foretz
pave the way for development of next- ences, and testing is done in both male et al., 2010; Lien et al., 2014; Lu et al.,
generation drugs that directly target the and female animals (Miller et al., 2007; 2015; Zheng et al., 2012), and reduction
biology of aging. Here, we summarize Nadon et al., 2008). Major findings of the in DNA damage (Algire et al., 2012). Met-
the major reasons why metformin was ITP include that nordihydroguaiaretic formin favorably influences metabolic
chosen to initiate this research. acid and aspirin each increase lifespan and cellular processes closely associated
Targeting Health Span of male mice (Strong et al., 2008) and with the development of age-related con-
Interventions that target aging pathways acarbose and 17-a-Estradiol extend ditions, such as inflammation (Saisho,
are capable of dramatically extending life- mouse lifespan preferentially in males 2015), autophagy (Song et al., 2015; Xie

1060 Cell Metabolism 23, June 14, 2016 2016 Published by Elsevier Inc.
Cell Metabolism

Essay

formin to the diet (Anisimov et al., 2008,


2011; Cabreiro et al., 2013; De Haes
et al., 2014). It increases mean lifespan
in female outbred mice by 40% (Anisi-
mov et al., 2008). When started early in
life, mean lifespan was increased by
14%, but with initiation at older ages,
this effect declined (Anisimov et al.,
2011). Metformin delays the onset of car-
cinoma and extends lifespan by a mean of
8% in a breast cancer model (Anisimov
et al., 2010), and extends lifespan by
20% in a model of Huntingtons disease
(Ma et al., 2007) only in males. A more
recent study (Martin-Montalvo et al.,
2013) demonstrated that metformin in-
creased lifespan by 4%6% in different
mouse breeds. The effects on health
span indices such as time on rotarod, dis-
tance on treadmill, open field tests, cata-
ract index, oral glucose tolerance tests,
insulin tolerance, and cognitive function
(Allard et al., 2016) were improved by
30%. As expected in these studies,
metformin also increased AMPK activity
and increased antioxidant protection, re-
sulting in reductions in both chronic
Figure 1. Metformin Targets Multiple Pathways of Aging inflammation and accumulation of oxida-
The figure depicts schematically the current consensus within the biology of aging community as to tive damage (Martin-Montalvo et al.,
pathways that are important in order to target aging and indicates at which points metformin has been
2013), all of which may contribute to
shown to have effects (see text). Key take-away: outside of the cell (1, top), metformin has been shown to
affect the receptors for cytokines, insulin, IGF-1, and adiponectin, all pathways that are activated with health span and lifespan seen in animal
aging and, when modulated, are associated with longevity. (1) Intracellular (2, middle) metformin inhibits models.
the inflammatory pathway and activates AMPK, increasing inhibition of mTOR, which seems to be a major Not all studies have shown similar ef-
target to modulate aging. Through some of these mechanisms, it also modulates oxidative stress and
removes senescent cells (the mitochondrial pathways are not shown, and the mechanisms by which fects of metformin on life or health span.
metformin induces senescent cell removal remain unclear). (2) These processes jointly (3, bottom) affect Feeding metformin to Drosophila resulted
inflammation, cellular survival, stress defense, autophagy, and protein synthesis, which are major bio- in a robust activation of AMPK and re-
logical outcomes associated with aging/longevity. Adapted from Barzilai et al. (2012).
duced lipid stores, but did not increase
lifespan (Slack et al., 2012). One possibility
et al., 2011), and cellular senescence (Jad- inhibit mitochondrial complex 1. This inhi- is that the dose of metformin in this study
hav et al., 2013; Moiseeva et al., 2013). In bition may have multiple downstream was toxic. The dose of 1 mM is well above
C. elegans metformin extends lifespan by effects, but importantly, it would lead to the comparable dose range in humans,
several possible mechanisms including a change in the AMP/ATP ratio, which and indeed doses higher than this
the alteration of the microbiome, specif- then activates AMPK. This activation increased mortality. This is also the case
ically by changing microbial folate and maybe relevant to metformins known in mammals. When using a 10-fold in-
methionine metabolism (Cabreiro et al., effect on hepatic glucose production crease in the dose that showed benefit in
2013). To date, there is no evidence for (through decreased gluconeogenesis), mice, mortality increased (Martin-Mon-
such effects in humans. Also, other inves- but it also may suppress lipid synthesis talvo et al., 2013). Smith et al. (2010) did
tigators have suggested additional mech- and exert insulin-sensitizing effects, re- not demonstrate increased lifespan in
anisms for metformin actions (De Haes sulting in decreased plasma insulin levels metformin-treated rats, although the high
et al., 2014; Onken and Driscoll, 2010) and decreased mTOR activity. However, dose used (15 times the dose used in hu-
supporting widely pleotropic effects. it is also possible that the singular effect mans) may have been toxic. Additionally,
It is currently unclear whether metfor- of metformin has not yet been identified, the investigators used caloric restriction
min has multiple effects on multiple path- and therefore metformins mechanisms as a positive control and failed to observe
ways or whether its observed effects of action are worth further investigation. the expected increased lifespan.
reflect downstream consequences of a Beyond these cellular processes, there
primary action on a single mechanism of is a growing body of evidence that metfor- Human Studies of Metformin that
aging. For example, an attractive expla- min can delay aging and increase healthy Target Age-Related Diseases
nation suggests (Foretz et al., 2014) that lifespan in vivo, specifically in nematodes If metformin can target and delay aging,
the primary action of metformin is to and several rodent strains by adding met- its administration should be associated

Cell Metabolism 23, June 14, 2016 1061


Cell Metabolism

Essay

with fewer age-related diseases in gen- out (e.g., most studies have been con- lowest risk was seen in those with
eral, rather than merely the decreased ducted in patients with diabetes and longer-term (> 6 years) metformin use
incidence of a single disease. Data from include an active comparator, which (Ng et al., 2014). A large observational
several randomized clinical trials and mul- could itself be cardio-toxic). Metformins study of metformin-treated T2DM pa-
tiple observational studies provide evi- potential CVD benefitsparticularly in tients reported lower rates of dementia
dence for such an effect, which would the area of primary preventionremain than in those treated with other diabetes
not be expected from glucose lowering an active area of research, including medications (Cheng et al., 2014). One
alone. an ongoing randomized trial in the UK study suggested that T2DM patients
Clinical Trials (The Glucose Lowering In Non-diabe- treated with metformin had increased
The Diabetes Prevention Program (DPP). tic hyperglycaemia Trial, GLINT, http:// risk for poor cognitive performance
The DPP was a randomized trial in U.S. www.isrctn.com/ISRCTN34875079; An- (Moore et al., 2013); however, it had a
adults at high risk for T2DM by virtue of fossi et al., 2010; Whittington et al., 2013). number of methodological flaws (Alagiak-
obesity and impaired glucose tolerance Observational Studies Suggest rishnan et al., 2013) and has not been
(Knowler et al., 2002). Over 3,000 subjects Metformin Decreases Cancer replicated. In one small clinical trial,
were randomly assigned to placebo, met- Incidence T2DM patients with depression (n = 58)
formin (850 mg twice daily), or a lifestyle- Several epidemiologic studies have were treated with metformin or placebo
modification program. Metformin reduced shown that metformin use is associated for 24 weeks (Guo et al., 2014). The met-
the incidence of T2DM by 31% compared with reduced cancer incidence and mor- formin group showed improved cognitive
to placebo over a mean follow-up of 3 tality (Landman et al., 2010; Lee et al., performance and reduced depressive
years and was effective in all age cate- 2011; Libby et al., 2009; Monami et al., symptoms, concurrent with improved
gories in preventing diabetes, defined by 2011; Tseng, 2012). While one meta-anal- glycemic control. In an unpublished trial,
HbA1C level, including the 20% who ysis (Stevens et al., 2012) did not show non-diabetic subjects (n = 80) with mild
were age 60 or older at baseline (Knowler that metformin prevents cancer, a more cognitive impairment showed significant
et al., 2015). Further, metformin treatment thorough analysis that included more improvements in some cognitive domains
was associated with improvement in car- data and accounted for heterogeneous after 12 months of metformin treatment
diovascular disease (CVD) risk factors comparators showed that overall cancer (Luchsinger et al., 2016). No definitive
(Goldberg et al., 2013; Haffner et al., incidence was reduced by 31% and can- trials have been conducted.
2005) and subclinical atherosclerosis (cor- cer mortality by 34% (Gandini et al., Association of Metformin with
onary artery calcium) in male participants 2014). There is also evidence from studies Decreased Mortality
(Goldberg et al., 2015). performed both in vitro and in vivo of met- A recent study (Bannister et al., 2014)
The United Kingdom Prospective Dia- formins role in attenuating tumorigenesis used retrospective observational data
betes Study. Patients with T2DM allo- (Anisimov and Bartke, 2013; Karnevi et al., from the UK Clinical Practice Research
cated to metformin compared with 2013; Liu et al., 2011; Quinn et al., 2013; Datalink. Patients with T2DM who were
conventional treatment had risk reduction Salani et al., 2012; Tosca et al., 2010). treated with metformin or sulphonylurea
of 20% (p = 0.032) for CVD and 42% (p = The mechanisms proposed relate to (SU) monotherapy were compared to
0.017) for diabetes-related death (UKPDS reduced insulin levels, improved insulin separate age- and sex-matched control
Group, 1998). This evidence from UKPDS action, decreased IGF-1 signaling, and groups without diabetes. SU-treated pa-
provides rationale for metformins de- activation of AMPK. Numerous ongoing tients had lower survival than both
signation as first-line therapy for most studies are testing the effect of metformin matched non-diabetic controls and met-
patients with T2DM. as adjuvant cancer therapy, with a formin-treated diabetic patients. Surpris-
Other Trials. In the HOME trial of insulin- recently published trial showing negative ingly, metformin-treated diabetic patients
treated T2DM patients, addition of metfor- results in advanced pancreatic cancer had survival rates similar to (and, among
min resulted in 40% reduction (compared (Kordes et al., 2015). Although no trials those age > 70, even better than) their
with placebo) in a CVD composite after 4 yet have reported effects of chronic treat- matched non-diabetic control group,
years of follow-up (Kooy et al., 2009). In ment on cancer prevention, studies in despite the fact that the diabetic patients
non-diabetic subjects, the GIPS III study early-stage cancer or pre-malignancy were more obese and had greater co-
(Lexis et al., 2014) failed to demonstrate suggest this may be fruitful (DeCensi morbidities at baseline. Mortality benefits
the benefit of short-term metformin treat- et al., 2015). have also been described in other obser-
ment (4 months) on left ventricular ejection Association of Metformin with vational studies and long-term follow-up
fraction, major adverse cardiovascular Better Cognitive Function of the UKPDS cohort, which showed
events, and mortality in post-myocardial Emerging evidence suggests that metfor- 36% reduction in all-cause mortality in
infarction patients, and the CAMERA trial min may preserve cognitive function. In the metformin treatment group (p =
(Preiss et al., 2014) showed no effect of the Singapore Longitudinal Aging Study, 0.011) (UKPDS Group, 1998). Not all
metformin (18 months) on carotid intimal metformin use was associated with a studies have been positivefor example,
medial thickness. 51% reduced risk of cognitive impairment an analysis from the Medicare Current
Observational Studies (defined by modified Mini-Mental Status Beneficiary Survey showed only a non-
The majority of observational data sup- Exam score % 23), which remained statistically significant survival benefit for
port metformin benefit in CVD, but resid- robust to adjustment for vascular and metformin-treated patients (Tinetti et al.,
ual bias and confounding cannot be ruled non-vascular risk factors. Further, the 2015).

1062 Cell Metabolism 23, June 14, 2016


Cell Metabolism

Essay

Considerations in Designing Human opment of even better pharmacologic ap- B12 Deficiency in the Diabetes Prevention Pro-
gram Outcomes Study. J. Clin. Endocrinol. Metab.
Metformin Trials proaches that will ultimately reduce 101, 17541761.
Dosing. While metformin can be prescribed healthcare costs related to aging.
at dosages of up to 2,250 mg/day, no Bannister, C.A., Holden, S.E., Jenkins-Jones, S.,
Morgan, C.L., Halcox, J.P., Schernthaner, G., Mu-
further effects of decreasing glucose are ACKNOWLEDGMENTS kherjee, J., and Currie, C.J. (2014). Can people with
noted after 1,6001,700 mg/day. After a type 2 diabetes live longer than those without? A
The American Federation for Aging Research has comparison of mortality in people initiated with
single oral dose, metformin is rapidly metformin or sulphonylurea monotherapy and
supported the TAME initiative. This work was sup-
distributed to many tissues following partial ported by the Nathan Shock Center of Excellence matched, non-diabetic controls. Diabetes Obes.
absorption by the small intestine, but the for the Biology of Aging (P30AG038072, N.B.), Metab. 16, 11651173.
luminal concentration in the gastrointes- the Glenn Center for the Biology of Human Aging
Bartke, A., Wright, J.C., Mattison, J.A., Ingram,
(Paul Glenn Foundation for Medical Research)
tinal tract remains high. After a single D.K., Miller, R.A., and Roth, G.S. (2001). Extending
(N.B.), grant 1R24AG044396 from the National the lifespan of long-lived mice. Nature 414, 412.
1.5 g dose, the peak plasma concentration Institute on Aging (NIA) (PI, Kirkland; co-PI, N.B.),
of 18 mM occurs in 3 hr, with a mean and grant P30 AG021332 from the NIA to the Barzilai, N., Huffman, D.M., Muzumdar, R.H., and
plasma half-life of about 20 hr (Foretz Wake Forest Older Americans Independence Bartke, A. (2012). The critical role of metabolic
Center (S.B.K.). pathways in aging. Diabetes 61, 13151322.
et al., 2014). It is suggested, however, that
an equivalent dose for mice would be up Batandier, C., Guigas, B., Detaille, D., El-Mir, M.Y.,
REFERENCES Fontaine, E., Rigoulet, M., and Leverve, X.M.
to 10-fold higher. Studies on biodistribution (2006). The ROS production induced by a
of metformin in mice showed accumulation Alagiakrishnan, K., Sankaralingam, S., Ghosh, M., reverse-electron flux at respiratory-chain complex
mainly in the gastrointestinal tract, kidney, Mereu, L., and Senior, P. (2013). Antidiabetic drugs 1 is hampered by metformin. J. Bioenerg. Bio-
and their potential role in treating mild cognitive membr. 38, 3342.
and liver.
impairment and Alzheimers disease. Discov.
Safety. Metformin has been used with Med. 16, 277286. Bridges, H.R., Jones, A.J., Pollak, M.N., and Hirst,
an excellent safety record for over 60 J. (2014). Effects of metformin and other bigua-
Algire, C., Moiseeva, O., Deschenes-Simard, X., nides on oxidative phosphorylation in mitochon-
years. Side effects are monitored closely Amrein, L., Petruccelli, L., Birman, E., Viollet, B., dria. Biochem. J. 462, 475487.
within clinical trials, and the safety of met- Ferbeyre, G., and Pollak, M.N. (2012). Metformin
reduces endogenous reactive oxygen species Cabreiro, F., Au, C., Leung, K.Y., Vergara-Irigaray,
formin use in DPP/DPPOS was reported N., Cocheme, H.M., Noori, T., Weinkove, D.,
and associated DNA damage. Cancer Prev. Res.
on in 2012, when over 18,000 patients- (Phila.) 5, 536543. Schuster, E., Greene, N.D., and Gems, D. (2013).
years of follow-up had accrued, and by Metformin retards aging in C. elegans by altering
Allard, J.S., Perez, E.J., Fukui, K., Carpenter, P., In- microbial folate and methionine metabolism. Cell
which time 20% of the cohort was age gram, D.K., and de Cabo, R. (2016). Prolonged 153, 228239.
70 or older (mean age 64). There were metformin treatment leads to reduced transcrip-
tion of Nrf2 and neurotrophic factors without Cheng, C., Lin, C.H., Tsai, Y.W., Tsai, C.J., Chou,
no cases of lactic acidosis or significant P.H., and Lan, T.H. (2014). Type 2 diabetes and
cognitive impairment in older C57BL/6J mice.
hypoglycemia (Diabetes Prevention Pro- Behav. Brain Res. 301, 19. antidiabetic medications in relation to dementia
gram Research Group, 2012). Mild diagnosis. J. Gerontol. A Biol. Sci. Med. Sci. 69,
Anfossi, G., Russo, I., Bonomo, K., and Trovati, M. 12991305.
anemia occurred in 12% of metformin- (2010). The cardiovascular effects of metformin:
treated participants versus 8% in the further reasons to consider an old drug as a corner- Cho, K., Chung, J.Y., Cho, S.K., Shin, H.W., Jang,
stone in the therapy of type 2 diabetes mellitus. I.J., Park, J.W., Yu, K.S., and Cho, J.Y. (2015). Anti-
placebo group (p = 0.04). Vitamin B12 hyperglycemic mechanism of metformin occurs
Curr. Vasc. Pharmacol. 8, 327337.
deficiency occurred in 7% of metformin via the AMPK/LXRa/POMC pathway. Sci. Rep. 5,
group versus 5% in placebo group after Anisimov, V.N., and Bartke, A. (2013). The key role 8145.
of growth hormone-insulin-IGF-1 signaling in aging
13 years; risk of B12 deficiency increases and cancer. Crit. Rev. Oncol. Hematol. 87, de Cabo, R., Carmona-Gutierrez, D., Bernier, M.,
with duration of use but was not greater in 201223. Hall, M.N., and Madeo, F. (2014). The search for
antiaging interventions: from elixirs to fasting regi-
older compared with younger subjects in Anisimov, V.N., Berstein, L.M., Egormin, P.A., Pis- mens. Cell 157, 15151526.
DPPOS (Lalau et al., 1990). Further, the kunova, T.S., Popovich, I.G., Zabezhinski, M.A.,
risk of lactic acidosis appears to be Tyndyk, M.L., Yurova, M.V., Kovalenko, I.G., De Haes, W., Frooninckx, L., Van Assche, R.,
Poroshina, T.E., and Semenchenko, A.V. (2008). Smolders, A., Depuydt, G., Billen, J., Braeckman,
related to renal function, not age per se, Metformin slows down aging and extends life B.P., Schoofs, L., and Temmerman, L. (2014). Met-
and is currently considered to be very span of female SHR mice. Cell Cycle 7, 27692773. formin promotes lifespan through mitohormesis via
the peroxiredoxin PRDX-2. Proc. Natl. Acad. Sci.
low (Aroda et al., 2016). Anisimov, V.N., Egormin, P.A., Piskunova, T.S., USA 111, E2501E2509.
In the TAME study, we plan to enroll Popovich, I.G., Tyndyk, M.L., Yurova, M.N., Zabez-
3,000 subjects, ages 6579, in 14 cen- hinski, M.A., Anikin, I.V., Karkach, A.S., and Roma- DeCensi, A., Puntoni, M., Guerrieri-Gonzaga, A.,
nyukha, A.A. (2010). Metformin extends life span of Cazzaniga, M., Serrano, D., Lazzeroni, M., Vin-
ters across the U.S. Rather than study HER-2/neu transgenic mice and in combination giani, A., Gentilini, O., Petrera, M., Viale, G., et al.
the effects of metformin on each separate with melatonin inhibits growth of transplantable (2015). Effect of Metformin on Breast Ductal Carci-
tumors in vivo. Cell Cycle 9, 188197. noma In Situ Proliferation in a Randomized Presur-
condition, we will measure time to a new
gical Trial. Cancer Prev. Res. (Phila.) 8, 888894.
occurrence of a composite outcome that Anisimov, V.N., Berstein, L.M., Popovich, I.G.,
includes cardiovascular events, cancer, Zabezhinski, M.A., Egormin, P.A., Piskunova, Diabetes Prevention Program Research Group
T.S., Semenchenko, A.V., Tyndyk, M.L., Yurova, (2012). Long-term safety, tolerability, and weight
dementia, and mortality. TAME will also M.N., Kovalenko, I.G., and Poroshina, T.E. (2011). loss associated with metformin in the Diabetes
assess important functional and geriatric If started early in life, metformin treatment in- Prevention Program Outcomes Study. Diabetes
end points. creases life span and postpones tumors in female Care 35, 731737.
SHR mice. Aging (Albany, N.Y.) 3, 148157.
If successful, TAME will mark a para- Duca, F.A., Cote, C.D., Rasmussen, B.A., Zadeh-
digm shift, moving from treating each Aroda, V.R., Edelstein, S., Goldberg, R., Knowler, Tahmasebi, M., Rutter, G.A., Filippi, B.M., and
W.C., Marcovina, S., Orchard, T., Bray, G.A., Lam, T.K. (2015). Metformin activates a duodenal
medical condition to targeting aging per Schade, D., Temprosa, M., White, N.H., et al. Ampk-dependent pathway to lower hepatic
se. We expect this to facilitate the devel- (2016). Long-term Metformin Use and Vitamin glucose production in rats. Nat. Med. 21, 506511.

Cell Metabolism 23, June 14, 2016 1063


Cell Metabolism

Essay
Fontana, L., and Partridge, L. (2015). Promoting hibition involves suppression of the IGF-I receptor Liu, B., Fan, Z., Edgerton, S.M., Yang, X., Lind,
health and longevity through diet: from model signalling pathway in human pancreatic cancer S.E., and Thor, A.D. (2011). Potent anti-prolifera-
organisms to humans. Cell 161, 106118. cells. BMC Cancer 13, 235. tive effects of metformin on trastuzumab-resistant
breast cancer cells via inhibition of erbB2/IGF-1 re-
Fontana, L., Partridge, L., and Longo, V.D. (2010). Kickstein, E., Krauss, S., Thornhill, P., Rutschow, ceptor interactions. Cell Cycle 10, 29592966.
Extending healthy life spanfrom yeast to humans. D., Zeller, R., Sharkey, J., Williamson, R., Fuchs,
Science 328, 321326. M., Kohler, A., Glossmann, H., et al. (2010). Bigua- Longo, V.D., Antebi, A., Bartke, A., Barzilai, N.,
nide metformin acts on tau phosphorylation via Brown-Borg, H.M., Caruso, C., Curiel, T.J., de
Foretz, M., Hebrard, S., Leclerc, J., Zarrinpashneh, mTOR/protein phosphatase 2A (PP2A) signaling. Cabo, R., Franceschi, C., Gems, D., et al. (2015).
E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, Proc. Natl. Acad. Sci. USA 107, 2183021835. Interventions to Slow Aging in Humans: Are We
F., and Viollet, B. (2010). Metformin inhibits hepatic Ready? Aging Cell 14, 497510.
gluconeogenesis in mice independently of the Knowler, W.C., Barrett-Connor, E., Fowler, S.E.,
LKB1/AMPK pathway via a decrease in hepatic en- Hamman, R.F., Lachin, J.M., Walker, E.A., and Lu, J., Shi, J., Li, M., Gui, B., Fu, R., Yao, G., Duan,
ergy state. J. Clin. Invest. 120, 23552369. Nathan, D.M.; Diabetes Prevention Program Z., Lv, Z., Yang, Y., Chen, Z., et al. (2015). Activa-
Research Group (2002). Reduction in the incidence tion of AMPK by metformin inhibits TGF-b-induced
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., and of type 2 diabetes with lifestyle intervention or met- collagen production in mouse renal fibroblasts. Life
Viollet, B. (2014). Metformin: from mechanisms of formin. N. Engl. J. Med. 346, 393403. Sci. 127, 5965.
action to therapies. Cell Metab. 20, 953966.
Knowler, W.C., Eldelstein, S.L., Goldberg, R.B., Luchsinger, J.A., Perez, T., Chang, H., Mehta, P.,
Gandini, S., Puntoni, M., Heckman-Stoddard, Ackermann, R.T., Crandall, J.P., Florez, J.C., Steffener, J., Pradabhan, G., Ichise, M., Manly,
B.M., Dunn, B.K., Ford, L., DeCensi, A., and Szabo, Fowler, S.E., Herman, W.H., Horton, E.S., Kahn, J., Devanand, D.P., and Bagiella, E. (2016). Metfor-
E. (2014). Metformin and cancer risk and mortality: S.E., et al.; Diabetes Prevention Program Research min in Amnestic Mild Cognitive Impairment: Re-
a systematic review and meta-analysis taking into Group (2015). HbA1c as a predictor of diabetes sults of a Pilot Randomized Placebo Controlled
account biases and confounders. Cancer Prev. and as an outcome in the diabetes prevention pro- Clinical Trial. J. Alzheimers Dis. 51, 501514.
Res. (Phila.) 7, 867885. gram: a randomized clinical trial. Diabetes Care 38,
5158. Ma, T.C., Buescher, J.L., Oatis, B., Funk, J.A., Nash,
Goldberg, R., Temprosa, M., Otvos, J., Brunzell, J., A.J., Carrier, R.L., and Hoyt, K.R. (2007). Metformin
Marcovina, S., Mather, K., Arakaki, R., Watson, K., Kooy, A., de Jager, J., Lehert, P., Bets, D., Wulffele, therapy in a transgenic mouse model of Hunting-
Horton, E., and Barrett-Connor, E. (2013). Lifestyle M.G., Donker, A.J., and Stehouwer, C.D. (2009). tons disease. Neurosci. Lett. 411, 98103.
and metformin treatment favorably influence lipo- Long-term effects of metformin on metabolism
protein subfraction distribution in the Diabetes Pre- and microvascular and macrovascular disease in Martin-Montalvo, A., Mercken, E.M., Mitchell, S.J.,
vention Program. J. Clin. Endocrinol. Metab. 98, patients with type 2 diabetes mellitus. Arch. Intern. Palacios, H.H., Mote, P.L., Scheibye-Knudsen, M.,
39893998. Med. 169, 616625. Gomes, A.P., Ward, T.M., Minor, R.K., Blouin, M.J.,
et al. (2013). Metformin improves healthspan and
Goldberg, R., Temprosa, M., Aroda, V.R., Barrett- Kordes, S., Pollak, M.N., Zwinderman, A.H., Ma- lifespan in mice. Nat. Commun. 4, 2192.
Connor, E.L., Budoff, M., Crandall, J., Dabelea, thot, R.A., Weterman, M.J., Beeker, A., Punt,
D., Horton, E.S., Mather, K.J., Orchard, T.J., et al. C.J., Richel, D.J., and Wilmink, J.W. (2015). Met- Miller, R.A., Harrison, D.E., Astle, C.M., Floyd, R.A.,
(2015). Effect of long-term interventions in the Dia- formin in patients with advanced pancreatic Flurkey, K., Hensley, K.L., Javors, M.A., Leeuwen-
betes Prevention Program (DPP) and its Outcome cancer: a double-blind, randomised, placebo- burgh, C., Nelson, J.F., Ongini, E., et al. (2007). An
Study on coronary artery calcium (CAC). Diabetes controlled phase 2 trial. Lancet Oncol. 16, Aging Interventions Testing Program: study design
64, Supplement 1A, LB5. 839847. and interim report. Aging Cell 6, 565575.

Guo, M., Mi, J., Jiang, Q.M., Xu, J.M., Tang, Y.Y., Lalau, J.D., Vermersch, A., Hary, L., Andrejak, M., Miller, R.A., Harrison, D.E., Astle, C.M., Baur, J.A.,
Tian, G., and Wang, B. (2014). Metformin may pro- Isnard, F., and Quichaud, J. (1990). Type 2 dia- Boyd, A.R., de Cabo, R., Fernandez, E., Flurkey,
duce antidepressant effects through improvement betes in the elderly: an assessment of metformin K., Javors, M.A., Nelson, J.F., et al. (2011). Rapa-
of cognitive function among depressed patients (metformin in the elderly). Int. J. Clin. Pharmacol. mycin, but not resveratrol or simvastatin, extends
with diabetes mellitus. Clin. Exp. Pharmacol. Phys- Ther. Toxicol. 28, 329332. life span of genetically heterogeneous mice.
iol. 41, 650656. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191201.
Landman, G.W., Kleefstra, N., van Hateren, K.J.,
Haffner, S., Temprosa, M., Crandall, J., Fowler, S., Groenier, K.H., Gans, R.O., and Bilo, H.J. (2010). Moiseeva, O., Deschenes-Simard, X., St-Germain,
Goldberg, R., Horton, E., Marcovina, S., Mather, Metformin associated with lower cancer mortality E., Igelmann, S., Huot, G., Cadar, A.E., Bourdeau,
K., Orchard, T., Ratner, R., and Barrett-Connor, in type 2 diabetes: ZODIAC-16. Diabetes Care V., Pollak, M.N., and Ferbeyre, G. (2013). Metfor-
E.; Diabetes Prevention Program Research Group 33, 322326. min inhibits the senescence-associated secretory
(2005). Intensive lifestyle intervention or metformin phenotype by interfering with IKK/NF-kB activa-
on inflammation and coagulation in participants Lee, M.S., Hsu, C.C., Wahlqvist, M.L., Tsai, H.N., tion. Aging Cell 12, 489498.
with impaired glucose tolerance. Diabetes 54, Chang, Y.H., and Huang, Y.C. (2011). Type 2 dia-
15661572. betes increases and metformin reduces total, colo- Monami, M., Colombi, C., Balzi, D., Dicembrini, I.,
rectal, liver and pancreatic cancer incidences in Giannini, S., Melani, C., Vitale, V., Romano, D.,
Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, Taiwanese: a representative population prospec- Barchielli, A., Marchionni, N., et al. (2011). Metfor-
J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkin- tive cohort study of 800,000 individuals. BMC min and cancer occurrence in insulin-treated type
son, J.E., Frenkel, K., Carter, C.S., et al. (2009). Cancer 11, 20. 2 diabetic patients. Diabetes Care 34, 129131.
Rapamycin fed late in life extends lifespan in genet-
ically heterogeneous mice. Nature 460, 392395. Lexis, C.P., van der Horst, I.C., Lipsic, E., Wieringa, Moore, E.M., Mander, A.G., Ames, D., Kotowicz,
W.G., de Boer, R.A., van den Heuvel, A.F., van der M.A., Carne, R.P., Brodaty, H., Woodward, M.,
Harrison, D.E., Strong, R., Allison, D.B., Ames, Werf, H.W., Schurer, R.A., Pundziute, G., Tan, E.S., Boundy, K., Ellis, K.A., Bush, A.I., et al.; AIBL Inves-
B.N., Astle, C.M., Atamna, H., Fernandez, E., Flur- et al.; GIPS-III Investigators (2014). Effect of met- tigators (2013). Increased risk of cognitive impair-
key, K., Javors, M.A., Nadon, N.L., et al. (2014). formin on left ventricular function after acute ment in patients with diabetes is associated with
Acarbose, 17-a-estradiol, and nordihydroguaia- myocardial infarction in patients without diabetes: metformin. Diabetes Care 36, 29812987.
retic acid extend mouse lifespan preferentially in the GIPS-III randomized clinical trial. JAMA 311,
males. Aging Cell 13, 273282. 15261535. Nadon, N.L., Strong, R., Miller, R.A., Nelson, J.,
Javors, M., Sharp, Z.D., Peralba, J.M., and Harri-
Jadhav, K.S., Dungan, C.M., and Williamson, D.L. Libby, G., Donnelly, L.A., Donnan, P.T., Alessi, son, D.E. (2008). Design of aging intervention
(2013). Metformin limits ceramide-induced senes- D.R., Morris, A.D., and Evans, J.M. (2009). New studies: the NIA interventions testing program.
cence in C2C12 myoblasts. Mech. Ageing Dev. users of metformin are at low risk of incident Age (Dordr.) 30, 187199.
134, 548559. cancer: a cohort study among people with type 2
diabetes. Diabetes Care 32, 16201625. Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M.,
Johnson, S.C., Rabinovitch, P.S., and Kaeberlein, Abudayyeh, A., Rodrigues Hoffman, A., and Safe,
M. (2013). mTOR is a key modulator of ageing Lien, F., Berthier, A., Bouchaert, E., Gheeraert, C., S. (2014). Mechanism of metformin-dependent in-
and age-related disease. Nature 493, 338345. Alexandre, J., Porez, G., Prawitt, J., Dehondt, H., hibition of mammalian target of rapamycin (mTOR)
Ploton, M., Colin, S., et al. (2014). Metformin inter- and Ras activity in pancreatic cancer: role of spec-
Karnevi, E., Said, K., Andersson, R., and Rose- feres with bile acid homeostasis through AMPK- ificity protein (Sp) transcription factors. J. Biol.
ndahl, A.H. (2013). Metformin-mediated growth in- FXR crosstalk. J. Clin. Invest. 124, 10371051. Chem. 289, 2769227701.

1064 Cell Metabolism 23, June 14, 2016


Cell Metabolism

Essay
Ng, T.P., Feng, L., Yap, K.B., Lee, T.S., Tan, C.H., tion in non-small-cell lung cancer cells. FASEB J. Tosca, L., Rame, C., Chabrolle, C., Tesseraud, S.,
and Winblad, B. (2014). Long-term metformin us- 26, 788798. and Dupont, J. (2010). Metformin decreases IGF1-
age and cognitive function among older adults induced cell proliferation and protein synthesis
with diabetes. J. Alzheimers Dis. 41, 6168. Slack, C., Foley, A., and Partridge, L. (2012). Acti- through AMP-activated protein kinase in cultured
vation of AMPK by the putative dietary restriction bovine granulosa cells. Reproduction 139,
Onken, B., and Driscoll, M. (2010). Metformin mimetic metformin is insufficient to extend lifespan 409418.
induces a dietary restriction-like state and the in Drosophila. PLoS ONE 7, e47699.
oxidative stress response to extend C. elegans Tseng, C.H. (2012). Diabetes, metformin use, and
Healthspan via AMPK, LKB1, and SKN-1. PLoS colon cancer: a population-based cohort study in
Smith, D.L., Jr., Elam, C.F., Jr., Mattison, J.A.,
ONE 5, e8758. Taiwan. Eur. J. Endocrinol. 167, 409416.
Lane, M.A., Roth, G.S., Ingram, D.K., and Allison,
D.B. (2010). Metformin supplementation and life UK Prospective Diabetes Study (UKPDS) Group
Perez-Revuelta, B.I., Hettich, M.M., Ciociaro, A., span in Fischer-344 rats. J. Gerontol. A. Biol. Sci.
Rotermund, C., Kahle, P.J., Krauss, S., and Di (1998). Effect of intensive blood-glucose control
Med. Sci. 65, 468474. with metformin on complications in overweight
Monte, D.A. (2014). Metformin lowers Ser-129
phosphorylated a-synuclein levels via mTOR- patients with type 2 diabetes (UKPDS 34). Lancet
Song, Y.M., Lee, Y.H., Kim, J.W., Ham, D.S., Kang, 352, 854865.
dependent protein phosphatase 2A activation.
E.S., Cha, B.S., Lee, H.C., and Lee, B.W. (2015).
Cell Death Dis. 5, e1209.
Metformin alleviates hepatosteatosis by restoring Whittington, H.J., Hall, A.R., McLaughlin, C.P.,
SIRT1-mediated autophagy induction via an Hausenloy, D.J., Yellon, D.M., and Mocanu, M.M.
Preiss, D., Lloyd, S.M., Ford, I., McMurray, J.J.,
AMP-activated protein kinase-independent (2013). Chronic metformin associated cardiopro-
Holman, R.R., Welsh, P., Fisher, M., Packard,
pathway. Autophagy 11, 4659. tection against infarction: not just a glucose
C.J., and Sattar, N. (2014). Metformin for non-dia-
lowering phenomenon. Cardiovasc. Drugs Ther.
betic patients with coronary heart disease (the
Stevens, R.J., Ali, R., Bankhead, C.R., Bethel, 27, 516.
CAMERA study): a randomised controlled trial.
Lancet Diabetes Endocrinol. 2, 116124. M.A., Cairns, B.J., Camisasca, R.P., Crowe, F.L.,
Farmer, A.J., Harrison, S., Hirst, J.A., et al. (2012). Wilkinson, J.E., Burmeister, L., Brooks, S.V., Chan,
Cancer outcomes and all-cause mortality in adults C.C., Friedline, S., Harrison, D.E., Hejtmancik, J.F.,
Quinn, B.J., Dallos, M., Kitagawa, H., Kunnumak- Nadon, N., Strong, R., Wood, L.K., et al. (2012).
kara, A.B., Memmott, R.M., Hollander, M.C., Gills, allocated to metformin: systematic review and
collaborative meta-analysis of randomised clinical Rapamycin slows aging in mice. Aging Cell 11,
J.J., and Dennis, P.A. (2013). Inhibition of lung 675682.
tumorigenesis by metformin is associated with trials. Diabetologia 55, 25932603.
decreased plasma IGF-I and diminished receptor Xie, Z., Lau, K., Eby, B., Lozano, P., He, C., Pen-
tyrosine kinase signaling. Cancer Prev. Res. (Phila.) Strong, R., Miller, R.A., Astle, C.M., Floyd, R.A., nington, B., Li, H., Rathi, S., Dong, Y., Tian, R.,
6, 801810. Flurkey, K., Hensley, K.L., Javors, M.A., Leeuwen- et al. (2011). Improvement of cardiac functions by
burgh, C., Nelson, J.F., Ongini, E., et al. (2008). chronic metformin treatment is associated with
Saisho, Y. (2015). Metformin and Inflammation: Its Nordihydroguaiaretic acid and aspirin increase life- enhanced cardiac autophagy in diabetic OVE26
Potential Beyond Glucose-lowering Effect. En- span of genetically heterogeneous male mice. mice. Diabetes 60, 17701778.
docr. Metab. Immune Disord. Drug Targets 15, Aging Cell 7, 641650.
196205. Zheng, Z., Chen, H., Li, J., Li, T., Zheng, B., Zheng,
Tinetti, M.E., McAvay, G., Trentalange, M., Cohen, Y., Jin, H., He, Y., Gu, Q., and Xu, X. (2012). Sirtuin
Salani, B., Maffioli, S., Hamoudane, M., Parodi, A., A.B., and Allore, H.G. (2015). Association between 1-mediated cellular metabolic memory of high
Ravera, S., Passalacqua, M., Alama, A., Nhiri, M., guideline recommended drugs and death in older glucose via the LKB1/AMPK/ROS pathway and
Cordera, R., and Maggi, D. (2012). Caveolin-1 is adults with multiple chronic conditions: population therapeutic effects of metformin. Diabetes 61,
essential for metformin inhibitory effect on IGF1 ac- based cohort study. BMJ 351, h4984. 217228.

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