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> Supplementary Table 1 Summary of all published compound testing studies
> using
> healthy, long-lived rodents and lifespan as an endpointa
> Compoundb Dosage Study information and evaluation Refs.
> ?-Lipoic acid
>
>

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Supplementary Table 1 Summary of all published compound testing studies using
healthy, long-lived rodents and lifespan as an endpointa
Compoundb Dosage Study information and evaluation Refs.
?-Lipoic acid

Defined isocaloric diets: lipoic acid (600 mg/kg diet) or CoQ10 (100 mg/kg diet)
Male B6C3F1 (n=60 each group) mice fed defined diets in defined amounts containing
lipoic acid or CoQ10 from 14 mo of age had no increase in lifespan.
Evaluation: ?-Lipoic acid and coenzyme Q10 produced no LS effects. This is an
unambiguous study design. (Lee et al. 2004)

?-Lipoic acid

Diet supplemented with 1.5 g/kg ?-lipoic acid

Male BN rats switched from CR to AL feeding at 12 mo old of age to an ?-lipoic
acid supplemented diet had somewhat extended survival versus those shifted to
a diet without ?-lipoic acid (n=24 or more). The authors conclude ?-lipoic acid
preserves a physiological ``memory'' of CR. However, the CR rats are smaller
and weigh less (and therefore likely eat less) than control rats. Food consumption
after the cessation of CR was not reported or measured.
Evaluation: The LS extension effects attributed to ?-lipoic acid are most likely
due to ongoing CR. (Merry et al. 2008)

Acetyl-l-carnitine (AC)

75 mg/kg bw/d in water

Sixteen-mo-old F344 male rats maintained at each of 3 sites (n=15 at each site)
were fed lab chow AL. Pooled survival data found a significant increase in LS
with treatment. The bw of the AC rats was significantly less than control at
one site.
Evaluation: AC increases rat LS, but a CR effect cannot be excluded by the data.
(Markowska et al. 1990)

N-acetyl-L-cysteine (NAC)

Administered in drinking water at either 5 or 10 g/L beginning at 7 mo of age
Both concentrations of NAC significantly increased the LS of male but not female
HET3 mice (n=16 of each sex). Both food and water consumption were reduced by
NAC treatment, suggesting NAC may induce voluntary CR.
Evaluation: NAC increased mouse LS significantly in males, but this effect may
be due to voluntary CR. (Flurkey et al. 2010)

Aminoguanidine

Fed orally in food at 65 mg/kg bw/d
Aminoguanidine fed isocalorically to male B6C3F1 mice had no effect on LS or
bw (n=60 each group).
Evaluation: Aminoguanidine has no effect on the LS of mice. (Spindler Mote 2007)

Aminoguanidine and ?-lipoic acid fed together

Fed orally in food at 65 and 73 mg/kg bw/d, respectively
Evaluation: At the concentrations used, the combination of aminoguanidine and
?-lipoic acid had no effect on the LS or bw of male B6C3F1 mice fed isocalorically
with controls (n=60 each group).
Evaluation: The combination of aminoguanidine and ?-lipoic acid has no effect
on the LS of mice. (Spindler Mote 2007)

Aminoguanidine, ?-lipoic acid, pregnenolone, and coenzyme Q10 fed together

Aminoguanidine, ?- lipoic acid, pregnenolone, and coenzyme Q10 at 65, 73, 0.2,
and 12 mg/kg bw/d, respectively, in food Evaluation: Isocaloric feeding of the
combination of aminoguanidine, ?-lipoic acid, pregnenolone and coenzyme Q10 together
had no effect on the LS or bw of male B6C3F1 mice (n=60 each group).
Evaluation: The combination of aminoguanidine, ?-lipoic acid, pregnenolone and
coenzyme Q10 had no effect on the LS of mice.
(Spindler Mote 2007)

Antioxidant mixture (AM)

AM fed daily mixed with diet. See next column for details.

AM feeding begun at 2 and 9 mo of age produced a 9.5% to 16% increase in mean
and max LS of male B6 mice. Bw measured monthly or bimonthly. ``The results...showed
that both experimental and control mice [were] equally varied in weight (data
not given).'' The meaning of this statement is unclear. Induced CR cannot be
excluded as source of the LS increase.
AM delivered 7.5 mg ?-carotene; 15 mg ?-tocopherol acetate; 50 mg ascorbic acid;
25 Myg sodium selenite; 38.4 mg zinc gluconate (5 mg elemental zinc); 25 mg rutin
(quercetin 3 ?-rutinoside)/kg bw/d
Evaluation: AM mixture increased LS significantly. However, a voluntary CR cannot
be excluded as the cause. (Bezlepkin et al. 1996)

Aspirin

21 mg/kg food (3.3 mg/kg bw/d)

Aspirin begun at 4 mo of age significantly increased the median LS of HET3 mice
by 8%. Food consumption was not measured. The weights of the mice were described
as not different than control. However, no data or analyses were shown. Study
utilized large sample sizes, both sexes, and multiple testing sites.
Evaluation: Aspirin administered beginning at a younger age increased mouse LS
without affecting bw. A CR effect appears unlikely. (Strong et al. 2008)

Aspirin

21 mg/kg food (3.3 mg/kg bw/d)

Aspirin begun at 16-18 mo of age had no effect on the LS of female (n=60) HET3
mice. Males were not tested. No significant effect on bw detected (measurements
made every 3 mo, and statistics reported).
Evaluation: Aspirin begun late in life has no effect on the LS of female mice.
(Flurkey et al. 2010)

Angiotensin-converting enzyme (ACE) inhibitor Enalapril

20, 10 and 5 mg/L administered in water AL.

At all three concentrations, enalapril extended the LS of CF1 mice to the same
extent relative to the controls (n=21). This is a seriously confounded study.
Survival of controls was only 70-75% at 10 mo, 50% at 18 mo and 20% at 24 mo.
Bw was measured only at death or at 24 mo of age. The study was discontinued
at 24 mo of age, when all mice were killed. Food was administered AL, and not
measured. The control mice weighed ~35 g, while all the treated groups weighed
~47 g. The mean LS reported in this study (~548 d) is much shorter than that
reported elsewhere for this mouse strain (Kahn 1975).
Evaluation: The results of this study are inconclusive. Bw and its measurement
are confounded. Husbandry confounds are suggested, especially in view of the
studies cited below. (Ferder et al. 1993)

ACE inhibitor; Enalapril

Enalapril administered in food beginning at 120 d of age at 120 mg/kg food (~20
mg/kg bw/d)
Enalapril had no effect on the median or max LS of UM-HET3 mice. Study is robust
in its use of large sample sizes, testing in both sexes, and distribution of
studies over three testing sites. However, food consumption was not measured.
The weights of the mice were described as not different than control, but no
data or analyses were reported.
Evaluation: At the concentration used, enalapril had no effect on LS. However,
food intake was not measured and weight data and analysis are not presented.
(Harrison et al. 2009)

ACE inhibitor; Enalapril

Enalapril administered in drinking water from 30 d of age at 10 mg/kg bw/d

Enalapril treatment produced a significant 15% decrease in bw gain of Wistar
rats compared to control (vehicle consuming) rats (n=20). Food and water intake
and bw were determined weekly. Caloric intake was significantly reduced by enalapril.
At the 26 mo of age end point, the chow and vehicle treated rats had 20% and
the enalapril treated rats 45% survival.
Evaluation: At the concentration used, enalapril appeared to extend LS. A decrease
in food consumption and bw suggests a CR effect is responsible. (Santos et
al. 2009)

BAPN
(?-aminopropiontrile fumarate)

10 mg/d in water from 40 to 93 wk of age, and 5 mg/d thereafter
At the concentration used, BAPN had no effect on the LS of male or female CD*F
rats. The statistical power is low (n=5 males and 5 females/group). Air conditioner
failure led to deaths of some mice. In some studies, higher concentrations of
BAPN caused irreversible inhibition of growth and lowered bw.
Evaluation: At the concentration used, BAPN did not extend LS. A number of serious
study confounds exist, reducing confidence in the results. (Kohn Leash 1967)

BAPN

BAPN administered at 1 or 3 mg/mL in drinking water beginning at 2-mo of age
for 6, 12 or 18 mo.
Five of six groups of LAF/J mice (n=24) treated with BAPN showed an increase
in mean LS by ~2 mo of treatment. Mice treated with 3 mg/mL had lower bw than
controls. Survival curves could only be analyzed after ~40% of deaths occurred
due to unexplained early deaths. Voluntary CR cannot be excluded as source of
LS increase.
Evaluation: The results of a confounded study suggest BAPN may extend LS. However,
voluntary CR cannot be excluded. (LaBella Vivian 1978)

Boron

Starting at 794 d of age, mice were given 4.3 ppm or 21.6 ppm sodium borate
in drinking water Boron in drinking water beginning at 794 d of age had no effect
on the LS of male C57BL/6J mice. However, the authors point out that the boron
content of Purina #5001 is 31.1 ppm, much higher than the amount delivered in
the water.
Evaluation: A confounded study gave equivocal results. (Massie 1994)

Caffeic acid phenethyl ester (CAPE)

At 120 d of age, 30 and 300 mg/kg food (5 and 50 mg/kg bw/d)
CAPE had no effect on the median or max LS of UM-HET3 mice. Food consumption
was not measured. The weights of the mice were described as not different than
control, but no data or analyses were shown. Study utilized large sample sizes,
both sexes, and multiple testing sites.
Evaluation: At the concentration used, CAPE had no effect on LS. (Harrison
et al. 2009)

Centrophenoxine (Dimethylaminoethyl p-chlorophenoxyacetatecentrophenoxine 0.3
g of centrophenoxine/L drinking water from 8.6 to 18.2 mo of age and from 22.2
mo of age to death Centrophenoxine extended the median, mean and max LS of Swiss
Webster Albino mice (n?32) by ~30%, 27% (P=0.039) and 27%. However, drug treated
mice were ~11% lighter than the control mice at 22.4 mo of age, suggesting a
possible CR effect.
Evaluation: DMEA extends mouse LS, probably by inducing voluntary CR. (Hochschild
1973)

Coenzyme Q10 (CoQ10)

10 mg/kg bw/d. CoQ was administered AL in food after being dissolved in soybean
oil. CoQ10 was less than 0.5 mg/kg/d in the control group. Male S-D rats (n=75/group)
and male C57/B17 mice (n=43/group) were fed CoQ10 supplemented diets starting
at 2 mo of age. No significant differences in LS were found. CoQ10 levels were
significantly elevated in the plasma and liver. Animals were weighed ``regularly''
and no differences were found. However, the weight data and their analysis were
not reported.
Evaluation: CoQ10 supplementation has no effect on mouse or rat lifespans at
this dosage. (Lonnrot et al. 1998)

Coenzyme Q10 (CoQ10)
Defined isocaloric diet with CoQ10 (100 mg/kg diet) Male B6C3F1 (n=60 each
group) mice fed defined diets in defined amounts containing lipoic acid or CoQ10
from 14 mo of age had no change in LS.
Evaluation: CoQ10 produced no LS effect at this concentration. (Lee et al. 2004)

Coenzyme Q10 (CoQ10)

0.7 mg/kg bw/d CoQ10 in food

Male Wistar rats (n=43/group) were fed AL with diets containing 61% polyunsaturated
fatty acids. One group was supplemented with CoQ10. CoQ10 extended mean LS by
~12% and max LS by 24%. Weights were measured and reported throughout the study,
and no significant effects were found. Food intake was reported as not different
than control, but no details or analyses were given. CoQ10 content was significantly
higher in the liver mitochondria of supplemented rats.
Evaluation: Low dose CoQ10 supplementation of rats on a high polyunsaturated
fatty acid diet appeared to extend lifespan, although a CR effect cannot be excluded.
(Quiles et al. 2004)

Coenzyme Q10 (CoQ10)

Zero, 93, or 371 mg of CoQ10 /kg bw fed AL in food.

Male C57BL/6 mice fed AL diets providing CoQ supplementation beginning at 3.5
mo of age (n=50/group). No significant LS difference was found between groups.
CoQ9 and CoQ10 in mitochondria and tissues of liver, heart, kidney, skeletal
muscle, (but not brain) increased with dosage and duration of supplementation.
Bw throughout study was reported, as was the method of their statistical analysis.
Bw was unaffected by supplementation.
Evaluation: At the concentrations used, CoQ10 supplementation had no effect on
LS or bw of male C57BL/6 mice. (Sohal et al. 2006)

Coenzyme Q10 (CoQ10)
See also in this table ?-Lipoic acid and coenzyme Q10 (Lee et al. 2004); and
coenzyme Q10, aminoguanidine, ?-lipoic acid, and pregnenolone fed together (Spindler
Mote 2007).

Creatine

Treated mice were fed a standard rodent diet containing 1% Creatine and control
mice were fed a standard diet. The mean LS of B6 mice was increased 9% and max
LS 3.5% by creatine (p<0.05; n=81/group). The weights of the mice or their food
consumption were not reported or discussed.
Evaluation: Creatine extends the LS of mice, but induced, voluntary CR cannot
be excluded.
(Bender et al. 2007)

Cysteine hydrochloride

0.5 and 1% in food

AKRc male (n=30) and C3Hd (n=29) female mice were fed AL two supplemented diets
from 1.5 to 16 mo of age. For AKR mice, 1% cysteine produced a 20% increase in
the age at which 50% of the mice were dead (from ~8 to ~10 mo; P<=0.01). No effect
was found with C3H mice. AKR and C3H mice are short-lived strains. Weights were
measured monthly and reported. No analysis of the weights was presented. Controls
consumed two different amounts of food.
Evaluation: Cysteine may have extend the LS of AKR mice. However, a CR effect
on LS cannot be excluded. The study is confounded by differential caloric intake
among the control mice and unanalyzed weight data. (Harman 1957)

Cysteine hydrochloride

1% in food

AKR male (n=42), C3H female (n=49) and Swiss male (n=48) mice were fed supplemented
diets AL from weaning to 16 mo of age. The half-survival time of AKR mice was
prolonged 14.5% (P < 0.1). However, cysteine had a slight adverse effect on the
LS of C3H and Swiss mice, although it is unclear whether this effect was statistically
significant. AKR and C3H mice are short-lived strains. Average weight was determined
monthly, and reported. No analysis or discussion of the weights was presented.

Evaluation: Cysteine hydrochloride may have extend the LS of the short-lived
AKR mouse strain, but shortened that of C3H and Swiss mice. These results are
consistent with those from of previous study. A CR effect on LS cannot be excluded.
(Harman 1961)

Cysteine hydrochloride

0.5 and 1% in food

Male LAFl mice were fed AL a custom, semi-synthetic diet with or without the
drug from of 6 to 8 wks of age (control n=120; treated n=60). The drug produced
no change in mean LS. The study is confounded by an increase in mortality induced
by the semi-synthetic diet which the decreased 50% survival of controls from
20 to 15 mo of age relative to chow diet; and an increase in mortality at about
14 mo of age due to ``poor animal care''.
Evaluation: In a multiply confounded study, cysteine hydrochloride had no effect
on the LS of a long-lived mouse strain. (Harman 1968)

Dehydro-epiandrosterone sulfate (DHEAS)
25 ?g/mL DHEAS in their drinking water AL
No increase in LS was detected in DHEAS treated mice fed control or CR diets.
Food consumption and weights were monitored. DHEAS did not affect bw or cancer
patterns.
Evaluation: At the concentration used, DHEAS has no effect on LS. (Pugh et al.
1999)

Deltaran [mixture of synthetic ?-sleep inducing peptide (DSIP; Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu)
and glycine (w/w, 1:10)] Deltaran injected at 100 mg/kg bw for 5 consecutive
d/mo

Max (17.1%; P<0.01; n=54) but not mean LS increased for female SHRe mice subcutaneously
injected with Deltaran. The mean LS of the treated mice was not increased. No
data on food consumption or bw given.
Evaluation: Deltaran extends max LS, but an induced, voluntary CR effect cannot
be excluded.
(Popovich et al. 2003)

Deprenyl [a.k.a. (-)Deprenyl; Selegiline; Carbex; Eldepryl)]

Oral (1.0 mg selegiline/kg food); equaling about 0.05 mg selegiline/kg bw/d

Oral deprenyl significantly increased LS in female Syrian hamsters (~20% increase;
p=0.02; n=35), but not in males. Female control hamsters had a shorter LS than
male controls, and deprenyl equalized their LS. Selegiline can be used orally
in Syrian hamsters because they do not degrade 90% of it in the first pass through
the liver as do mice and humans. No effect of selegiline on bw was found. Food
intake and bw were measured regularly, and these data were shown.
Evaluation: Oral deprenyl extends the LS of female Syrian hamsters. (Stoll et
al. 1997; Stoll et al. 1994)

Deprenyl [a.k.a. (-)Deprenyl; Selegiline; Carbex; Eldepryl)]
0.25 mg/kg s.c. three times a wk. Age at which the treatment started is not
given. Deprenyl increased the LS of castrated female Wistar rats by almost double
(P<0.05; n=9), but not intact rats. No food consumption or bw data.
Evaluation: Castration together with deprenyl increased the LS of female rats.
Induced, voluntary CR cannot be excluded. (Dallo 2001)

Deprenyl [a.k.a. (-)Deprenyl; Selegiline; Carbex; Eldepryl)]

Dissolved in saline and given by s.c. injection. at 0.25, 0.5, and 1.0 mg/kg/injection,
three times a wk. Deprenyl extended mean and max LS in male F344 rats (n=12/group).
Rats received deprenyl starting at 18 mo of age for 13 mo. Mean LS significantly
increased by 8.4% (0.25 mg/kg) and 5.6% (0.5 mg/kg). Rats given 1.0 mg/kg die
sooner than controls. Rats were fed AL.
Evaluation: Injected deprenyl extended the LS of male rats. However, an induced
CR effect cannot be excluded. No information regarding food consumption or bw
was provided. (Kitani et al. 2006; Kitani et al. 2005)

Deprenyl [a.k.a. (-)Deprenyl; Selegiline; Carbex; Eldepryl)] and Dinh lang (Polycias
fruticosum L.) root extract (DLRE) alone and together Mice received DLRE (10
mg/kg bw oral), deprenyl (0.25 mg/kg bw s.c.), DLRE plus deprenyl, or a saline
control three times/wk beginning at 12-mo-old Deprenyl and Dinh lang root extract
extended the mean LS of OFA-l mice (by 35 and 43%, respectively) and together
their effects were greater (64%). Max LS was similarly extended. The drugs did
not suppress food intake or change bw.
Evaluation: Oral deprenyl and Dinh lang root extract extends the LS of male OFA-l
mice.
(Yen Knoll 1992)

2,2'-Diaminodiethyl disulfide dihydrochloride (DDS)

0.5 and 1% in food

AKR male (n=25 or 30) and C3H (n=29) female mice were fed AL the two diets from
2 to 16 mo of age. For AKR mice, a 20% increase in ``half-survival time'' was
found with 0.5% DDS (from ~8 to ~10 mo; P<=0.01). No effect was found with C3H
mice. Weights were measured monthly and reported. No analysis of the weights
was presented. Controls consumed two different amounts of food.
Evaluation: DDS may have extend the LS of AKR mice. However a CR effect on LS
cannot be excluded. The study is confounded by possible differential caloric
intake among the control mice and unanalyzed weight data. (Harman 1957)

2,2'-Diaminodiethyl disulfide dihydrochloride (DDS)

1% in food

AKR male (n=43), C3H (n=48) female and Swiss male (n=51) mice were fed the supplemented
diet AL from after weaning to 16 mo of age. 1% DDS somewhat shortened the LS
of all 3 strains of mice, including that of AKR, which had experienced an increase
in LS when fed DDS at 0.5% in food (see above) (Harman 1957). Average weight
was determined monthly, and was reported. No analysis or discussion of the weights
was presented.
Evaluation: 1% DDS in food shortens the lifespan of mice. (Harman 1961)

Digoxin (Trade names: Lanoxin; Digitek; and Lanoxicaps)

12.5 mg Digoxin / kg of food.

Digoxin increased mean LS 29% in male and 14% in female mice. The survival curves
were rectangular. The control vs. treated males had average bw of 31.1 and 28.2
g; the control and treated females weights of 25.9 and 21.5 g. The hearts weighed
less in the treated groups.
Evaluation: Digoxin treatment extends mouse LS, apparently by inducing voluntary
CR. (Coburn et al. 1974)

Dinitrophenol (DNP)

Administered orally in drinking water (~1 mg/L DNP)

DNP treatment increased median LS 6.7% and mean LS by 7.1% (p=0.038). Food consumption
was measured and did not differ from control. Bw was reduced ~10%.
Evaluation: DNP slightly extended median and mean LS without changing food consumption.
However, bw was decreased, perhaps due to its well-described effect of uncoupling
oxidative phosphorylation. (Caldeira da Silva et al. 2008)

2,6-Di-tert-butyl hydroquinone

0.25 and 0.5% in food

Male LAFl mice were fed AL a custom, semi-synthetic diet from of 6 to 8 wks
of age (control n=120; treated n=60). The drug produced no change in mean LS.
The study is confounded by an increase in mortality induced by the semi-synthetic
diet, which the decreased 50% survival of controls from 20 to 15 mo of age relative
to a chow diet; and an increase in mortality at about 14 mo of age due to ``poor
animal care''.
Evaluation: In a multiply confounded study, 2,6-di-tert-butyl hydroquinone had
no effect on the LS of mice. (Harman 1968)

2,6-Di-tert-butyl-4-methylphenol (BHT; butylated hydroxytoluene)

0.25 and 0.5% in food

Male LAFl mice were fed AL a custom, semi-synthetic diet from of 6 to 8 wks
of age (control n=120; treated n=60). Both concentrations of BHT increased the
mean LS (by 45% for 0.50% BHT; P<0.01). But, BHT produced a 5-12% reduction in
bw, suggesting a CR effect on LS. The studies were confounded by an increase
in mortality induced by the custom, semi-synthetic diet, which the decreased
50% survival of controls from 20 to 15 mo of age relative to a chow diet; and
an increase in mortality at about 14 mo of age due to ``poor animal care''.
Evaluation: In a multiply confounded study, BHT extended the mean LS of mice.
However, it reduced bw dose responsively, suggesting a CR effect on LS. The synthetic
diet used induced early mortality, and poor animal care led to increased mortality
at 14 months of age. (Harman 1968)

2,6-Di-tert-butyl-4-methylphenol (BHT; butylated hydroxytoluene)

BHT at 0.75% in Purina Laboratory Chow

Male BALB/c mice fed AL, BHT containing food from 8 or 11 weeks of age had statistically
significant increases in mean survival relative to controls. The BHT consuming
mice were ``generally heavier'', although no data are shown, and no information
regarding weighing of the mice is given. Livers of treated mice had ``increased
liver size'' at necropsy. No data were shown. The increase in weight is in contrast
to the other BHT studies reviewed herein.
Evaluation: BHT may have increased the mean LS of BALB/c mice. A CR effect appears
unlikely, although relevant data are not shown. Treatment beginning at 8 vs
11 weeks of age was less effective at extending LS. (Clapp et al. 1979)

2,6-Di-tert-butyl-4-methylphenol (BHT; butylated hydroxytoluene)and MEA (2-mercaptoethylamine)
MEA 1% in diet. BHT 0.2% to 0.5% in food.
Weanling and retired breeder female B6 mice were fed MEA and BHT supplemented
diets AL. Neither produced clear difference in mean or max LS. Animals that
received MEA and BHT did not attain control weights.
Evaluation: MEA and BHT had no effect on mean or max LS. (Kohn 1971)

DMEA (a.k.a. Deanol; dimethylethanolamine; N,N-dimethyl-2-Aminoethanol; ?-dimethylaminoethyl
alcohol; ?-hydroxyethyldimethylamine). A hydrolysis product of centrophenoxine
Administered orally in water; 86 ?g of dimethylaminoethanol acetamidobenzoate/mL
(equivalent to ~7 mg dimethylaminoethanol/kg bw/d
DMEA extended mean remaining life by 50% (P=0.018) and max LS by 11% when administered
to ~21 mo old male A/J mice (n=57 each group). However, the treated group had
5% lower bw than controls after treatment.
Evaluation: DMEA extends mean and max LS. Induced, voluntary CR is likely responsible.

(Hochschild 1973)

DOPA [L-dopa (levodopa, L-3,4-dihydroxyphenylalanine)]

Fed 1.0 or 40 mg Ldopa/kg bw in food (ground Purina chow) AL

Four to 5 wk-old, male Swiss albino mice fed L-DOPA weighed less and lived longer.
The LS study was terminated at 19 mo of age. The survivors were no Ldopa, 39%;
1 mg/g bw, 38%; 40 mg/g bw, 73% (P < 0.001). After 3 wk, ``differences in food
consumption among surviving animals tended to disappear; body weight tended to
show a gain''.
Evaluation: Oral DOPA extends LS and at least initially reduces bw and food intake.
Whether DOPA extends LS in the absence of CR is difficult to judge from the data
given. (Cotzias et al. 1974)

DOPA [L-dopa (levodopa, L-3,4-dihydroxyphenylalanine)]

L-dopa in 5 mg increments from 1 to 100 mg/g diet fed AL. The max concentration
that caused no deaths was 40 mg/g diet for males and 80 mg/g diet for females.
Male Swiss Albino mice (n=100/group) treated with 1.0, 20, and 40 mg/g diet L-dopa
starting from 4-5 wk of age had a dose dependant increase in median and mean
LS. Food consumption was reported as not significantly different. However, a
significant decrease in weight was reported in treated mice. During 1st mo of
treatment, the 40 mg/g diet group weighed 66.2 +/- 7.6% (mean +/- SD) of control
bw.
Evaluation: DOPA extends LS, reduces bw, but does not change food consumption.
DOPA may induce a discordance between bw and food consumption. See earlier study
above (Cotzias et al. 1974). (Cotzias et al. 1974)

Echinacea purpurea root extract

The extract was fed in the chow at 2 mg/mouse/d from 7 wk until just beyond
13 mo of age

Echinacea purpurea root extract in food may have increased the LS of BALB/cByJ
male mice eating AL. The LS curves of treated and untreated crossed at about
300 d of age. The authors arbitrarily chose a point when the curves diverged
to end the experiment. At this time more Echinacea-consuming mice were alive.
The authors do not report accurate measurements of food consumption or bw.
Evaluation: Echinacea purpurea may increase the survival of mice, although a
CR effect and a technical bias in the results cannot be excluded. (Brousseau
Miller 2005)

Emoxipine [2-ethyl-6-methyl-3-hydroxypyridine hydrochloride]

100-150 mg/kg (method of delivery and diet used were not specified).

Two mo old female SHK mice (n=112, control=118), C3HA mice (n=90, control=170),
AKR mice (n=50, control=50), and (C57BL X CBA)F1 mice (n=200, control=200) were
treated with 100-150 mg/kg emoxipine in an unspecified manner. Mean and max LS
of treated C3HA and SHK mice were increased significantly. in AKR and (C57BLxCBA)F1
mice there was no effect on LS. No bw or food intake data were provided. The
method of drug delivery and the diet used are not specified. The article references
Russian language journals which are not readily available.
Evaluation: Emoxipine extends the LS of C3HA, and SHK mice. However induced,
voluntary CR cannot be excluded. This study would be difficult to repeat. (Emanuel
Obukhova 1978)

Enterosorption - dietary sorbent (SKN sorbent: non-coated nitrogen-containing
carbon)
Administered in 10 d courses at 1 mo intervals in a dosage of 10 ml/kg bw
Male Wistar rats fed a sorbent containing diet starting at 28 mo of age had
a significant increase in mean and max LS. Food intake and bw were not reported.
These data appear to be published in two different places (Frolkis et al. 1984;
Frolkis et al. 1989).
Evaluation: Entrosorption extended the LS of male Wistar rats, but induced, voluntary
CR cannot be excluded as the cause. (Frolkis et al. 1989; Frolkis et al. 1984)

Epithalamin (low-molecular weight pineal peptide preparation)

The dosages are difficult to interpret as is the composition of Epithalamin
(see Study information and evaluation) Epithalamin injection on 5 consecutive
d/mo increased the mean LS of outbred female rats (strain not specified) by 6.2%.
A citation describing the preparation and composition of Epithalamin, in Russian
was not readily available. No information regarding food intake or bw was presented.
Evaluation: Epithalamin may have increased rat LS, however induced voluntary
CR cannot be excluded as the cause. This study would be difficult to repeat.
(Anisimov et al. 1992)

Epithalone (a synthetic Ala-Glu-Asp-Gly peptide)

Subcutaneous injections of 0.1 ?g Epithalone, 5 times a wk in 0.1 ml saline
beginning at 4 mo of age.

Group 1 female LIO rats were maintained on a 12h dark:light cycle (LD); Group
2, were maintained on illumination mimicking that at Petrozavodsk State University
(NL); and Group 3 were maintained on constant light (LL) (n=40 to 55/group).
Half of each of the 3 groups received Epithalon or vehicle. Epithalone had no
effect on mean LS. Epithalone reduced the max LS of LD rats but increased the
max LS of NL and LL rats relative to LD rats. No information regarding food intake
or bw was given.
Evaluation: Epithalone may increase the max LS of photoperiod stressed rats,
although a CR effect cannot be excluded because neither food intake nor bw were
reported. (Vinogradova et al. 2007)

Epithalone (a synthetic Ala-Glu-Asp-Gly peptide)

Subcutaneous injections of 0.1 ?g Epithalone, 5 times a wk in 0.1 ml saline
beginning at 4 mo of age.
Male LIO rats were maintained on 3 different dark:light regimen (see Study information
and evaluation of (Vinogradova et al. 2007), above. Half of each group received
Epithalon. The peptide had no significant effect on mean or max LS. No information
regarding food intake or bw were presented.
Evaluation: Epithalone does not increase the LS of control or photoperiod stressed
male rats. These results appear at odds with those cited immediately above.
(Vinogradova et al. 2008)

Exercise and sulfamerazine

Exercise AL and fed Sulfamerazine at 250 mg/kg in diet

Sulfamerazine (a sulfa antibiotic) extended the LS of rats (strain not specified)
significantly (~20%). The treated rats were 11% (males) and 36% (females) heavier
than controls. Sulfamerazine treated, exercising rats were considerably heavier
than controls. Food consumption was not measured.
Evaluation: Sulfamerazine extended rat LS. However, its effects, and the effects
of exercise on bw are counterintuitive. Sulfamerazine may reduce energy expenditure
or increase food consumption and extend lifespan. Alternatively, the drug may
have mitigated a bacterial pathogen in the animal colony. (Sperling et al. 1978)

n-6/n-3 Fatty acid ratio

Control chow diet and chow diet enriched with sunflower oil (n-6 rich; 750 g/6
kg pellets) or salmon oil (n-3 rich; 750 g/6 kg pellets) was fed AL. No effect
on LS was found when 10 mo old (n=12-14), female C57BL/6 mice were fed diets
containing either n-6 enriched or n-3 enriched chow. The control group weighed
significantly less than the treated mice.
Evaluation: Differences in the ratio of n-6/n3 fatty acids do not appear to influence
mouse LS.

(Valencak Ruf 2010)

n-6/n-3 Fatty acid ratio

Food was adjusted to an n-6/n-3 ratio of either 1, 4, or 16, but with a constant
polyunsaturated to monounsaturated to saturated fatty acid ratio. Three groups
of 33 Wistar rats were fed the various food containing fatty acids with different
n-6 to n-3 ratios AL from 4 wk of age. There were no significant differences
mean life span, food intake, or bw among the groups.
Evaluation: Variations in n-6/n-3 Fatty acid ratios do not alter mouse LS.

(Takeuchi et al. 2009)

Flumazenil (a.k.a. flumazepil, Ro 15-1788, Anexate, Lanexat, Mazicon, Romazicon)
3 to 4 mg/kg/d in drinking water acidified to pH 3.0)

Flumazenil treatment of F344 rats from 13 to 25 mo of age (n=20/group) significantly
increased the age to which 16 of the rats in each group survived by approximately
2 mo. No food consumption or bw data were reported.
Evaluation: Flumazenil may have increased the LS of rats, but induced, voluntary
CR cannot be excluded as the cause. (Marczynski et al. 1994)

Fluoro-deprenyl [(-)p-fluoro-deprenyl]

6-mo old male Wistar rats treated with 0.01 mg/kg bw, s.c.

Injection of fluoro-deprenyl (n = 40) or saline (n = 20) three times a wk for
25 mo resulted in 3 of 20 saline-treated and 15 of 40 drug-treated males surviving
to 24 mo of age (p=0.05). No food consumption or weight data were reported. (p-Fluoro-L-deprenyl
is a halogenated derivative of L-deprenyl which is almost indistinguishable in
potency and pharmacology)
Evaluation: Fluoro-deprenyl may have extended the LS of Wistar rats, but induced,
voluntary CR cannot be excluded as the means. (Dallo Knoll 1992)

Ginkgo biloba extract (GE) (EGb 761; ``most widely used form of Ginkgo biloba
in clinical studies...standardized in its content of ginkgo flavone glycosides
and terpenoids'' Beginning at 2 mo of age GE was administered orally mixed with
3 mL of sweetened condensed milk vehicle at a dose of 50 mg/kg bw?f GE significantly
increased male F344 rat max LS by 8%. Caloric intake was controlled to maintain
adult bw at ~300 g. There was no significant difference in weight between the
treated and untreated control groups at the time of death.
Evaluation: GE extend the max LS of rats. An induced voluntary CR effect cannot
be excluded by the data given, but appears unlikely given the feeding procedures
used.
(Winter 1998)

Green tea polyphenols

Administered in water (80 mg/L) beginning at 13 mo of age.

The average LS of polyphenol treated male B6 mice was significantly longer than
that of control mice (6.4% increase; n=50 mice/group). Max LS was not significantly
different. No significant differences in bw among groups were found.
Evaluation: Green tea polyphenols may increase the mean LS of mice. An induced
voluntary CR effect cannot be excluded but appears unlikely. (Kitani et al.
2007)

High fat or high carbohydrate diet

High fat or high carbohydrate diets fed AL.

A high fat diet decreased average longevity. Results were highly significant
in male and less significant in female rats (strain not identified). Two experimental
diets, one high in carbohydrate and one high in fat were fed AL. Food consumption
was measured and reported (n=15/group). High fat fed rats consumed 4.8 and 5.7%
less total calories (males and females, respectively).
Evaluation: A high fat diet reduces rat LS. (French et al. 1953)

Hydroxylamine hydrochloride

1% and 2% in food

AKR male (n=42), C3H female (n=49), and Swiss male (n=48) mice were fed the
supplemented diets AL from weaning to 16 mo of age. The ``half survival time''
of AKR mice was increased 17% by 2% hydroxylamine (P<0.05). The other strains
were unaffected. AKR and C3H mice are short-lived strains while Swiss is a long-lived
strain. Average weights were determined monthly, and reported. No analysis or
discussion of the weights was presented.
Evaluation: Hydroxylamine extend the LS of the short-lived AKR mouse strain.
However, hydroxylamine had no effect on the LS of the normal, long lived Swiss
mouse. A CR effect on LS cannot be excluded by the data shown. (Harman 1961)

Hydroxylamine hydrochloride

1 and 2% in food

Male LAFl mice were fed AL a semi-synthetic diet formulated with or without
the drug from of 6 to 8 wks of age (control n=120; treated n=60). The drug produced
no change in mean LS. The study is confounded by an increase in mortality induced
by the semi-synthetic diet, which the decreased 50% survival of controls from
20 to 15 mo of age; and an increase in mortality at about 14 mo of age due to
``poor animal care''.
Evaluation: In a multiply confounded study, hydroxylamine hydrochloride had no
effect on the LS of mice. (Harman 1961)

Isoflavone soy protein diets (Low vs. high) substituted for casein diets

Low and high soy protein diets were 32 and 972 mg/kg diet fed AL

Mouse LS was increased by a low isoflavone diet in two strains of normal mice.
A high isoflavone diet increased LS in one strain of normal mice but reduced
the LS of another strain. Diets were fed AL. Weights were different in the groups
fed the different diets.
Evaluation: Soy isoflavones may extend the LS of some strains of mice, but the
effects of induced voluntary CR cannot be excluded. (Bartke et al. 2004)

Kombucha

Treatment oral 15% solution of kombucha beverage AL; control received water.
Kombucha consumption from weaning until death significantly increased the LS
of B6 mice by ~5% (males; n=15) and 2% (females; n=17). Mice were fed AL. Kombucha
significantly decreased the weight of both sexes. Signs of organ damage were
found in treated mice.
Evaluation: Kombucha increased mouse LS, but induced voluntary CR appears the
probable reason. (Hartmann et al. 2000)

Marine collagen peptides (MCPs; a protease hydrolysate of chum salmon skin collagen)
MCPs administered in food at 2.25, 4.5, or 9% (wt/wt), with proportionally resuced
diet protein. MCPs were administered to groups of 40, 5 wk old S-D (equal numbers
of males and females). Bw and food consumption were measured weekly to bi-weekly.
Mean LS was significantly increased by MCPs. Bw and their statistical analysis
were given, and there were no significant differences. There were no significant
differences in food consumption between the groups.
Evaluation: MCPs extend the mean LS of S-D rats. (Liang et al. 2010)

MEA (2-mercaptoethylamine) and BHT (butylated hydroxytoluene)
MEA 1% in diet. BHT 0.2% to 0.5% in diet.
Weanling and retired breeder female B6 mice were fed MEA and BHT supplemented
diets AL. Neither produced a clear difference in mean or max LS. Animals that
received MEA and BHT did not attain control weights.
Evaluation: MEA and BHT have no effect on mean or max LS. (Kohn 1971)

Melatonin

Fed orally in food at 41 Myg/kg bw/d
Melatonin (n=60 each group) had no effect on the LS or bw of male B6C3F1 mice
fed isocalorically with controls.
Evaluation: Melatonin did not effect the longevity of male B6C3F1 mice. (Spindler
Mote 2007)

Mercaptoethanol (2-mercaptoethanol; 2-ME)

0.5% in food

AKR male (n=25) and C3H female (n=28) mice consuming a drug containing diet
AL from 2.5 to 16 mo of age experienced no increase in ``half-survival time''.
Weights were measured monthly and reported. No analysis of the weights was presented.
Evaluation: 2-ME had no effect on the LS of AKR or C3H mice. The study is confounded
by possible differential caloric intake among the control mice and unanalyzed
weight data. (Harman 1957)

Mercaptoethanol (2-mercaptoethanol; 2-ME)

Administered orally in food AL at 0.25% of diet (w/w)

2-ME extended the mean and max LS of male BC3F1 mice (n=60/group) by ~12% and
~13%, respectively (p<0.005). Reported bw of the two groups were statistically
different at only one time point. Food consumption was not measured.
Evaluation: 2-ME extended the mean and max LS of mice while producing little
effect on bw. A CR effect cannot be excluded, but appears unlikely. (Heidrick
et al. 1984)

2-Mercaptoethylamine hydrochloride (MEA)

0.5 and 1% in food

AKR male (n=22 or 28) and C3H female (n=25 or 28) mice were fed AL the two diets
from 1 or 2 to 16 mo of age. For AKR mice, a 20% increase in ``half-survival
time'' was found with 1% 2-mercaptoethylamine (from ~8 to ~10 mo; P<=0.01). No
effect was found with C3H mice. Weights were measured monthly and reported. No
analysis of the weights was presented.
Evaluation: Cysteine may have extend the LS of AKR but not C3H mice. However,
a CR effect on LS cannot be excluded. The study is confounded by possible differential
caloric intake among the control mice and unanalyzed weight data. (Harman 1957)

2-Mercaptoethylamine hydrochloride (MEA)

1% in food

AKR male (n=42), C3H female (n=49) and Swiss male (n=48) mice were fed the supplemented
diet AL from after weaning to 16 mo of age. The ``half-survival time'' of C3H
mice was extended from 14.5 to 18.3 months (26%; P<0.01), in contrast to the
previous study (Harman 1957). Also in contrast to the previous study, MEA had
no effect on the half-survival time of AKR mice. MEA had no effect on the LS
of Swiss mice, a long-lived mouse strain. AKR and C3H mice are short-lived strains.
Average weight was determined monthly, and reported. No analysis or discussion
of the weights was presented.
Evaluation: MEA may have extend the LS of the short-lived C3H mouse strain. However,
these results contrast with a previous study by the same author. MEA had no effect
on the LS of the normal, long lived Swiss mouse strain. A CR effect on LS cannot
be excluded. (Harman 1961)

2-Mercaptoethylamine hydrochloride (MEA)

0.5 & 1% in food

Male LAFl mice were fed AL a commercial chow or a custom semi-synthetic diet
from of 6 to 8 wks of age (control n=120; treated n=60). No statistically significant
change in LS was found using the commercial chow. With the synthetic diet, 1%
MEA produced a 12% increase in mean LS (P<0.01). But, 0.5 and 1% MEA produced
a 6 and 12% reduction in bw in these mice, suggesting a CR effect on LS. The
studies also were confounded by an increase in mortality induced by the semi-synthetic
diet, which the decreased 50% survival of controls from 20 to 15 mo; and an increase
in mortality at about 14 mo of age due to ``poor animal care''.
Evaluation: In a multiply confounded study, MEA extended the mean LS of mice.
However, it reduced bw dose responsively, suggesting a CR effect on LS, the synthetic
diet induced early mortality, and poor animal care led to increased mortality
at 14 months of age. (Harman 1968)

Metformin

100 mg/kg in drinking water
(estimated dosage of ~10 mg/kg bw/d) Metformin extended the mean LS of female
SHR mice by ~38% and max LS by ~21%. Mice were fed AL. Metformin ``slightly modified
the food consumption'' and ``decreased bw after the age of 20 mo''.
Evaluation: Metformin extended mean and max LS, but an induced, voluntary CR
effect appears possible, even likely. (Anisimov et al. 2008b)

Metformin

300 mg/kg bw/d in their food

F344 rats were fed a diet containing metformin or a control diet AL. A control
group was pair fed with the metformin treated group. Bw and food intake were
measured weekly. Metformin did not significantly increase mean or max LS.
Evaluation: Metformin had no effect on the LS of F344 rats. (Smith, Jr. et
al. 2010)

N-acetylserotonin (NAS) combined with melatonin

Both given in drinking water at 2.5 mg/kg bw/d. Melatonin and NAS stock solutions
10 mg/mL in 1% Tween-20. Controls given solvent. C3H mice (n=20/group) treated
with the combination of NAS and melatonin had a ~20% increase in LS (males) (p<
0.01). No affect was found for females. Some of the studies were right censored.
Weights were not reported for the LS mice. However, in other studies of B6 mice
reported herein, NAS and melatonin reduced the weights of the mice, suggesting
food intake may have been reduced.
Evaluation: NAS and melatonin in combination increased the lifespan of male C3H
mice, but a CR effect appears probable. (Oxenkrug et al. 2001)

Nitroflurbiprofen (NFP)

200 mg/kg food (33 mg/kg bw/d)

NFP begun at 4 mo of age had no effect on the median or max LS of HET3 mice.
Study utilized large sample sizes, both sexes, and multiple testing sites. However,
food consumption was not measured. The weights of the mice were described as
not different than control. However, it is unclear whether these observations
are anecdotal or systematic.
Evaluation: NFP at this concentration has no effect on mouse LS. (Strong et
al. 2008)

Nitroflurbiprofen (NFP)

200 mg/kg food (33 mg/kg bw/d)

NFP begun at 16-18 mo of age had no effect on the LS of female HET3 mice (n=60;
males not tested). No significant effect on bw was detected (measurements made
every 3 mo, and statistics reported).
Evaluation: NFP at this concentration has no effect on the LS of female mice.
(Flurkey et al. 2010)

Nordihydroguaiaretic acid (NDGA)

2.5 g of NDGA/kg of food (~417 mg/kg bw/d)

NDGA begun at 9 mo of age significantly increased the median but not max LS
of male (but not female) UM-HET3 mice by 12%. No effect found on max LS. Food
consumption was not measured. The weights of the mice were described as not different
than control. Study utilized large sample sizes, both sexes, and multiple testing
sites.
Evaluation: NDGA increased mouse LS significantly without changing mouse weights.
A potential CR effect cannot be excluded. This dose of NDGA significantly decreased
the weight of isocalorically fed male B6C3F1 mice (Fig. 1). (Strong et al. 2008)

Nordihydroguaiaretic acid (NDGA)

2.5 g of NDGA/kg of food (~417 mg/kg bw/d)

NDGA begun at 16-18 mo of age had no effect on the LS of female UM-HET3 mice
(n=60; males were not tested). Food was given AL. No significant effect on bw
was detected (measurements made every 3 mo, and statistics reported).
Evaluation: NDGA begun at 17-18 mo of age had no effect on the LS of female mice.
(Flurkey et al. 2010)

N-tert-butyl-?-phenylnitrone (PBN)

0.25 mg/mL of PBN in drinking water

PBN treatment begun at 24.5 mo of age (n=50 each group) prolonged mean and max
LS of male B6 mice by about 3% (p<0.005). PBN administration beginning at 18.5
or 21.5 mo produced no LS extension. There was no effect on bw, which was measured
throughout study and reported. Food consumption was not measured.
Evaluation: PBN appears to modestly extend mean and max LS of male mice. An induced
voluntary CR effect cannot be excluded, but appears unlikely. (Saito et al.
1998)

N-tert-butyl-?-phenylnitrone derivative 4-OH-?-phenyl-N-tert-butyl nitrone (4-OH-PBN)
350 mg/kg food (~53 mg/kg bw/d)

4-OH-PBN begun at 4 mo of age had no effect on the median or max LS of HET3
mice. Study utilized large sample sizes, both sexes, and multiple testing sites.
The weights of the mice were described as not different than control, but no
data or analyses were shown.
Evaluation: 4-OH-PBN at this dose had no effect on LS. (Strong et al. 2008)

N-tert-butyl-?-phenylnitrone derivative 4-OH-?-phenyl-N-tert-butyl nitrone (4-OH-PBN)
315 mg/kg food (~52 mg/kg bw/d)

4-OH-PBN begun at 16-18 mo of age had no effect on the LS of female UM-HET3
mice (n=60/group; males were not tested). No significant effect on bw was detected,
measurements made every 3 mo, and statistics were reported.
Evaluation: 4-OH-PBN at this dose has no effect on the LS of female mice. (Flurkey
et al. 2010)

Nucleic acids

An unspecified volume of a chloroform saturated water solution containing DNA
at 3 mg/mL)and ``ordinary'' RNA at an unspecified concentration administered
weekly by injection in an unspecified manner Five control (untreated) and 5 rats
of an unspecified strain began treatment at 750 d of age. The diet and its manner
of administration was not described. All the untreated rats died before 900 d.
Four of the treated rats died between the ages of 1600 and 1900 d, and one lived
2250 d. No statistical analyses were reported. The treated rats were reported
to have gained 1.5-2.3 gm, but weights were not reported.
Evaluation: Too little information is given and too many confounds exist in this
report for the study to be repeated or evaluated productively.

(Odens 1973)

Phenformin

2 mg/d administered in 0.2 ml of tap water/mouse/d os 5 times/wk beginning at
3.5 mo of age. Chronic treatment of female C3H/Sn mice prolonged mean LS by 23%
and decreased spontaneous tumor incidence. Food intake and bw were not measured.
Evaluation: Phenformin extended the LS of female mice of this relatively short
lived strain, although an induced CR effect cannot be excluded. It is possible
that these studies were performed at the time that C3H mice were infected with
mouse mammary tumor virus. (Dilman Anisimov 1980)

Pineal factor extract (PF)

Subcutaneous injections 5 d/mo of 0.1 mg PF or normal saline from 3.5 or 12
mo of age.

PF administered to groups (n=30-41) of female Swiss-derived outbred SHR mice
beginning at 3.5 mo (young) or 12 mo (middle age) extended average and max LS
``of tumor-free young mice'' by 20% and by 17% for middle aged. No information
regarding food intake or bw was reported. The composition and method of preparation
of PE are published in difficult to obtain Russian language journals. The studies
would be difficult to repeat.
Evaluation: PF extends mouse LS, although an induced voluntary CR effect cannot
be excluded. This study would be difficult to repeat. (Anisimov et al. 1989)

Piperoxane

Beginning at 16 mo. intraperitoneal injections 3 mg/kg bw/d piperoxane or saline
every 48 hours for four mo. Piperoxane extended mean survival of F344 rats by
16.7%. This is a weakly powered (n=8) preliminary study. The methods section
refers to a paper for which no record could be found. Food was given AL. Food
consumption was not investigated. The article states there was no significant
difference in bw, but no data are given.
Evaluation: Piperoxane may extend rat LS, but an induced, voluntary CR effect
cannot be excluded. (Compton et al. 1995)

Pregnenolone and melatonin

Fed orally in food at 200 Myg/kg bw/d and 41 Myg/kg bw/d, respectively At the
concentrations used pregnenolone and melatonin together (n=60 each group) had
no effect on the LS or bw of male B6C3F1 mice fed isocalorically.
Evaluation: The concentrations of pregnenolone and melatonin used had no effect
on the longevity of mice. (Spindler Mote 2007)

Propyl gallate

0.25 & 0.5% in food

Male LAFl mice were fed AL a semi-synthetic diet formulated with or without
the drug from of 6 to 8 wks of age (control n=120; treated n=60). The drug produced
no change in mean LS. The study is confounded by an increase in mortality induced
by the semi-synthetic diet, which the decreased 50% survival of controls from
20 to 15 mo of age; and an increase in mortality at about 14 mo of age due to
``poor animal care''.
Evaluation: In a multiply confounded study, propyl gallate had no effect on the
LS of mice. (Harman 1968)

Rapamycin

Microencapsulated rapamycin administered at 600 d of age at 14 mg/kg food (~2.24
mg of rapamycin/kg body wt/d).

Rapamycin significantly extended the LS of HET3 mice by an average of 12.7%
for females and 9.3% for males. Max LS also was increased significantly. However,
food consumption was not measured. The weights of the mice were described as
not different than control, but no data or analysis were shown. A confound in
the pooled male data is that groups which were treated with rapamycin at 600
d already had lower mortality than the groups which served as controls. In a
later publication, many of these authors report that this concentration of rapamycin
reduced the bw of HET3 mice (Miller et al. 2010) (see below). Study utilized
large sample sizes, both sexes, and multiple testing sites.
Evaluation: Microencapsulated rapamycin increased mouse LS significantly. Weight
data and analysis were not shown. A later report by many of these same investigators
suggests that rapamycin decreases the weight of this strain of mouse. Thus, induced,
voluntary CR cannot be excluded, and may be a likely source of the longevity
effects. (Harrison et al. 2009)

Rapamycin

Rapamycin was administered in food (14 mg/kg)

Rapamycin administered from the age of 9 mo extended the max and median LS of
AL fed HET3 mice by 10% for males and 18% for females. The treatment reduced
the weight of the mice by ~10% in males and 6% in females.
Evaluation: Rapamycin may extend the LS of UM-HET3 mice, however a CR effect
on LS cannot be excluded, and appears likely. (Miller et al. 2010)

Reduced advanced glycation end product (AGE) containing diet

NIH-31 open formula diets were prepared identically except one was exposed to
70 to 75DGC for 1-2 m and 55DGC for 30 m, as per normal (Regular); the other
was prepared by exposure to 80DGC for 1 m (Low). C57BL6 male mice were isocalorically
fed Regular or Low diets from 4 mo of age. Food consumption and bw were monitored
regularly and reported. Mice fed the Low diet had a 15% and 6% extension of
median and max LS. The Low diet had a 50% reduction in AGEs.
Evaluation: LS was extended by the Low AGE diet.

(Cai et al. 2007)

Resveratrol

Resveratrol in food, approximate doses in mg/kg bw/d were: for standard diet,
7.9, 30.9 and 204; for EOD diet, 7.6 and 30.4 Resveratrol fed at 3 concentrations
beginning at 12 mo of age had no effect on the LS of male B6 mice consuming a
standard diet AL or EOD.
Evaluation: Resveratrol at low to high doses has no effect on the LS of mice
fed a normal diet or fed EOD.
(Pearson et al. 2008)

Resveratrol

300 and 1200 ppm food (50 and 200 mg/kg bw/d)
Resveratrol administered from the age of 9 mo had no effect on the LS of AL
fed, male and female HET3 mice. No data regarding weight or food consumption
given.
Evaluation: Resveratrol at low to high doses has no effect on the LS of mice.
(Miller et al. 2010)

Simvastatin

12 and 120 mg/kg food; 2 and 20 mg/kg bw/d
Simvastatin administered from the age of 9 mo had no effect on the LS of AL
fed, male and female HET3 mice. No data regarding weight or food consumption
were given. What was reported as not different than control.
Evaluation: Simvastatin at a low and a high dose has no effect on the LS of mice
fed a normal diet. (Miller et al. 2010)

SkQ1 (Mitochondria-targeted plastoquinone derivative)

SkQ1 in drinking water fresh each d at a dosage of 0.5, 5, or 50 nmol SkQ1/kg
bw/d

Administration of SkQ1 from 2 mo of age to female, outbred SHR mice may have
extend mean but not max LS at 5 nmol/kg bw/d. No evidence for statistical analysis
of these data could be found. Food was given AL, but the authors state that food
consumption and bw were not significantly different between groups. No methods,
data, or their analysis were given. SHR mice are a normal, but short lived strain.

Evaluation: SkQ1 may have extended mean LS of SHR mice, but a lack of statistical
analysis and methods information undermine confidence in the results. The possibility
of an induced, voluntary CR effect cannot be excluded. (Anisimov et al. 2008a)

Sodium chloride in diet

From weaning 0.51 mEq Na (0.03% NaCl); 9.96mEq Na(0.58% NaCl); and 24.60 mEq
Na(1.45% NaCl)/100 g of diet. Elevated NaCl had no effect on the LS of Albino
rats (n=30) fed a basic diet AL.
Evaluation: Enhanced NaCl concentrations had no effect on rat LS.

(Lee 1963)

Tetrahydrocurcumin

0.2% in diet (w/w)

B6 mice (n=50/group) which started a diet containing tetrahydrocurcumin at 13
mo of age had ~12% (P<0.01) longer average LS than control mice. Max LS was 6.5%
greater (P<0.01). There was a decrease in bw of 2 to 4% (P < 0.05) in the treated
mice.
Evaluation: Tetrahydrocurcumin increased LS, but an induced, voluntary CR effect
appears likely. (Kitani et al. 2007)

Thioproline (L-thiazolidine-4-carboxylic acid)
2.0 g/kg of food from 28 wk of age
Thioproline induced a 20% decrease in spontaneous food intake, a 10% decrease
in bw at 100 wk of age, and a 23-29% increase in median and max LS.
Evaluation: LS extension by thioproline was likely induced by voluntary CR.
(Navarro et al. 2007)

Thymic peptides and fragments of thymic hormones, thymic humoral factor (FTS),
thymopentin (TP5), TM4 (``an enzyme resistant variant of FTS'') and thymosin
(TH) and thymic tissue extracts. Dosages and routes of administration not specified.
Article states they were given weekly starting from 2 mo of age.

TM4 treated CFW mice had a 25% increase in LS. CFW, A/HEN and B6 mice were treated
with thymic tissue extract, FTS, TP5, TM4 and TH beginning at 2 mo of age. This
article is a two pages in length, and no details are given. The composition or
purification methods for the extracts are not provided. Neither food intake nor
bw were reported.
Evaluation: TM4 increased the survival of CFW mice, but the effects of induced,
voluntary CR cannot be excluded. These studies could not be repeated with the
information given in the publication. (Ghanta et al. 1990)

Thymogen (synthetic L-Glu-L-Trp)

Thymogen: subcutaneously injected dissolved in 0.2 ml of saline 5 times/wk for
12 mo
Five-mo-old outbred female LIO rats injected with thymogen (5 ?g/rats, n=44;
control, n=32) 5 times/wk for 12 mo had an increase in max LS (P<0.001), but
no change in mean LS. The publication states there was no change in bw, but
no data are shown, and food consumption was not measured.
Evaluation: Thymogen extended the max LS of female LIO rats, possibly without
altering bw. However, a potential voluntary CR effect cannot be excluded. (Anisimov
et al. 2000)

Thymus Factor (TF)

Subcutaneous injections 5 d/mo of 5 ?g TF in normal saline from 3.5 or 12 mo
of age.

A peptide isolated from thymus, TF, administered to female Swiss-derived outbred
SHR mice (n=30-41) beginning at 3.5 mo (young) or 12 mo (middle age) increased
LS ``of tumor-free young mice'' by 12% (P < 0.05) and the LS of middle-aged animals
by 15% (P <0.05). No information regarding caloric intake or bw is given. The
composition and method of preparation of TF is published in difficult to obtain
Russian language journals. The studies would be difficult to repeat.
Evaluation: TF extended mouse LS of female SHR mice, although induced, voluntary
CR cannot be excluded as the mechanism. This study would be difficult to repeat.
(Anisimov et al. 1989)

Vigconic 28 (VI-28; A Chinese herbal formula)

Fed AL in diet at 0.05 and 0.5% (wt/wt; 50-80 mg/kg bw) starting at 36 wk of
age until death
Treatment of male and female C57BL/6J mice (n=41-60) significantly extended
median LS by ~10%. Effects on bw are described as ``moderate''. Food intake
is not reported. (VI-28 is composed of Radix Ginseng, Cornu Cervi, Cordyceps,
Radix Salviae, Semen Allii, Fructus Cnidii, Fructus Evodiae, and Rhizoma Kaempferiae.)
Evaluation: VI-28 extended the LS male and female C57BL/6J mice. But, voluntary,
induced CR can not be excluded, and appears likely. (Ko et al. 2010)

Vilon (synthetic L-Lys-L-Glu)

Vilon: 0.1 ?g Vilon subcutaneously injected/mouse beginning at 6-mo of age for
5 d/mo. Control injected with saline. Vilon extend the max LS of female CBA
mice (n=60). Treated survivors at 22 and 23 mo were ~1.2- and 2.6-fold more numerous
than controls (p<0.01). The mean LS was not increased. No information was given
regarding food intake or weight.
Evaluation: Vilon increased max LS of female CBA mice, but an induced, voluntary
CR effect cannot be excluded. (Khavinson et al. 2000; Khavinson Anisimov 2000)

Vitamin C (ascorbic acid)

2% in food

AKR male (n=27) and C3H (n=28) female mice were fed an ascorbic acid containing
diet AL from 1 or 2.5 to 16 mo of age. No increase in the age at which 50% of
the mice are dead was found. Weights were measured monthly and reported. No analysis
of the weights was presented.
Evaluation: Vitamin C did not extend the LS of AKR or C3H mice. The study is
confounded by possible differential caloric intake among the control mice and
unanalyzed weight data. (Harman 1957)

Vitamin C (ascorbic acid)

1% ascorbic acid (1,430 mg/kg bw) in drinking water

Vitamin C at the concentration used increased the average LS of B6 male mice
by ~9% (P<0.05). Max LS increased 2.9%. The ascorbic acid treated mice weighed
6 to 7% less than the control mice. Food intake was not controlled or reported.
Evaluation: Vitamin C increased the LS of mice, but a CR effect appears likely.
(Massie et al. 1984)

Vitamin E (RRR-?-tocopherol)

2 or 200 mg of dl-?-tocopherol fed to rats consuming a diet with 15% coconut
oil (saturated fat diet), safflower oil (unsaturated fat diet) or a combination
of both (CFD) Vitamin E, at the concentration used, had little or no significant
effect on the LS of male Wistar rats. Vitamin E was the only antioxidant present
in the diets.
Evaluation: Vitamin E at the concentration used had little if any effect on the
LS of mice regardless of the degree of saturation of the fats in their diets.

(Porta et al. 1980)

Vitamin E (RRR-?-tocopherol)

dl-?-tocopherol, 25 mg/kg diet, sprayed over the food as a solution in diethyl
ether.

A slight increase in the LS of vitamin E supplemented LAF1 [(C57L x A)F1 hybrid]
mice was reported. Supplementation shortened the LS of C3H mice. Food intake
was not measured. The study reported there was no difference in the bw of treated
mice. However, no data or analysis are given. Studies were discontinued at 28
mo of age.
Evaluation: Vitamin E may have strain-specifically extended or shortened mouse
lifespan. Induced, voluntary CR cannot be excluded as the reason for the increase
in LS. (Blackett Hall 1981)

Vitamin E (RRR-?-tocopherol)

20, 40 and 400 mg/kg of vitamin E in standard chow, fed AL.
Standard chow contains 40 mg/kg vitamin E. Vitamin E, at the concentration used,
had no effect on the LS of female Balb/c mice (n=42 and 45/group). Mice were
fed vitamin E diets (apparently) from weaning. Neither weights nor food consumption
were reported. The age at which treatment was begun was not reported.
Evaluation: Vitamin E had no effect on the LS of female Balb/c mice at the concentration
tested.
(Morley Trainor 2001)

Vitamin E (RRR-?-tocopherol), glutathione, melatonin, and strawberry
extract

Vitamin E (500 ppm), glutathione (0.5%); vitamin E plus glutathione (500 ppm
+ 0.5%, respectively),melatonin (11 ppm), and strawberry extract (1%). Orally
in diet. Vitamin E, glutathione, melatonin, and strawberry extract combined
had no effect on LS at the concentrations tested. Male C57BL\6 mice were fed
AL supplemented AIN-76 diet beginning at 18 mo of age. Mice were killed at 24
mo of age or when 50% of the mice had died. No effect on mean LS was found. The
authors state, ``all the mice in this study were heavier than expected, no difference
in weight was observed between dietary groups'', which seems contradictory.
Evaluation: Vitamin E, glutathione, melatonin, and strawberry extract had no
effect on the mean LS of male C57BL\6 mice at the concentration tested. (Meydani
et al. 1998)

aThe author reviewed only English language publications for this review.
bAbbreviations: AL, Ad libitum; B6, C57BL/6; bw, body weight; d, day or days;
EOD, every other day; F344, Fischer 344; LS, lifespan; max, maximum; min, minutes;
mo, month or months; os, by mouth; wk, week or weeks; S-D, Sprague-Dawley.
cAKR mice are a normal strain with a short LS (~50% survival at 300 d).
dC3H mice are a short lived strain with a high breast cancer incidence. During
the era in which many of these studies were performed they were infected with
a vertically transmitted mammary tumor virus.
eSHR mice are a normal strain with a short LS (~50% survival at 350 d).
fThe notation ``mg/kg bw?'' indicates that the article did not make clear whether
it was reporting dose/kg diet or dose/kg body weight.

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