X-Message-Number: 21861
Date: Mon, 2 Jun 2003 20:17:52 -0700 (PDT)
From: Doug Skrecky <>
Subject: could lowering IGF-1 postpone "aging"?

Med Hypotheses 2003 Jun;60(6):784-92
 A low-fat, whole-food vegan diet, as well as other strategies that
down-regulate IGF-I activity, may slow the human aging process.

 A considerable amount of evidence is consistent with the proposition that
systemic IGF-I activity acts as pacesetter in the aging process. A
reduction in IGF-I activity is the common characteristic of rodents whose
maximal lifespan has been increased by a wide range of genetic or dietary
measures,including caloric restriction. The lifespans of breeds of dogs
and strains of rats tend to be inversely proportional to their mature
weight and IGF-I levels. The link between IGF-I and aging appears to be
evolutionarily conserved; in worms and flies, lifespan is increased by
reduction-of-function mutations in signaling intermediates homologous to
those which mediate insulin/IGF-I activity in mammals. The fact that an
increase in IGF-I activity plays a key role in the induction of sexual
maturity, is consistent with a broader role for-IGF-I in aging
regulation. If down-regulation of IGF-I activity could indeed slow aging
in humans, a range of practical measures for achieving this may be at
hand. These include a low-fat, whole-food, vegan diet, exercise training,
soluble fiber, insulin sensitizers, appetite suppressants, and agents
such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic
synthesis of IGF-I. Many of these measures would also be expected to
decrease risk for common age-related diseases.
 Regimens combining several of these approaches might have a sufficient
impact on IGF-I activity to achieve a useful retardation of the aging
process. However, in light of the fact that IGF-I promotes endothelial
production of nitric oxide and may be of especial importance to
cerebrovascular health, additional measures for stroke prevention-most
notably salt restriction-may be advisable when attempting to
down-regulate IGF-I activity as a pro-longevity strategy.
  Caloric restriction has been shown to increase longevity in organisms
ranging from yeast to mammals. In some organisms, this has been
associated with a decreased fat mass and alterations in
insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore
these associations with enhanced longevity, we studied mice with a
fat-specific insulin receptor knockout  (FIRKO). These animals have
reduced fat mass and are protected against
age-related obesity and its subsequent metabolic abnormalities, although
their food intake is normal. Both male and female FIRKO mice were found
to have an increase in mean life-span of approximately 134 days (18%),
with parallel increases in median and maximum life-spans. Thus, a
reduction of fat mass without caloric restriction can be associated with
increased longevity in mice, possibly through effects on insulin signaling.

Nutr Cancer 2002;43(2):187-92
 Dietary flaxseed inhibits human breast cancer growth and metastasis and
downregulates expression of insulin-like growth factor and epidermal
growth factor receptor.
 Recent studies indicate that diets rich in phytoestrogens and n-3 fatty
acid have anticancer potential. This study determined the effect of
flaxseed (FS), the richest source of lignans and alpha-linolenic acid, on
growth and metastasis of established human breast cancer in a nude mice
model. Estrogen receptor-negative human breast cancer cells, MDA-MB-435,
were injected into the mammary fat pad of mice (Ncr nu/nu) fed a basal
diet (BD). At Week 8, mice were randomized into two diet groups, such
that the groups had similar tumor size and body weight. One continued on
the BD, while the other was changed to BD supplemented with 10% FS, until
sacrifice at Week 15. A significant reduction (P < 0.05) in tumor growth
rate and a 45% reduction (P = 0.08) in total incidence of metastasis were
observed in the FS group. Lung metastasis incidence was 55.6% in the BD
group and 22.2% in the FS group, while the lymph node metastasis incidence
was 88.9% in the BD group and 33.3% in the FS group (P < 0.05). Mean
tumor number (tumor load) of total and lymph node metastasis was
significantly lower in the FS than in the BD group (P < 0.05). Metastatic
lung tumor number was reduced by 82%, and a significantly lower tumor
trend (P < 0.01) was observed in the FS group. Lung weight, which also
reflects metastatic tumor load, in the FS group was reduced by 20% (P <
0.05) compared with the BD group. Immunohistochemical study showed that
Ki-67 labeling index and expression of insulin-like growth factor I and
epithelial growth factor receptor in the primary tumor were lower in the
FS (P < 0.05) than in the BD group. In conclusion, flaxseed inhibited the
established human breast cancer growth and metastasis in a nude mice
model, and this effect is partly due to its downregulation of
insulin-like growth factor I and epidermal growth factor receptor expression.

Cancer Epidemiol Biomarkers Prev 2002 Sep;11(9):852-61
 Dietary correlates of plasma insulin-like growth factor I and
insulin-like growth factor binding protein 3 concentrations.
Plasma levels of insulin-like growth factor I (IGF-I) have been
associated with risk of several cancers. Although protein-calorie
malnutrition is known to decrease IGF-I levels, few published studies
have related diet to IGF-I levels in well-nourished humans. We examined
the cross-sectional association of plasma IGF-I and IGF-binding protein 3
(IGFBP-3) levels with intakes of alcohol, energy, macronutrients,
micronutrients, and specific foods in 1037 healthy women. Adjusted mean
hormone levels across categories of dietary variables were calculated by
linear regression. Results were adjusted for non-dietary factors found to
be associated with IGF levels. Total energy intake was positively
associated with IGF-I levels when adjusted for covariates. Adjusted mean
levels of IGF-I (ng/ml) across increasing quintiles of energy intake were
181, 185, 191, 199, and 195 (P for the linear trend = 0.006). In other
multivariate analyses, energy-adjusted fat and carbohydrate intake had no
association with IGF-I levels. The most consistent finding was a positive
association between protein intake with circulating IGF-I concentration
(174, 188, 201, 192, and 196 ng/ml across quintiles of protein intake; P =
0.002), which was largely attributable to milk intake. Adjusted mean
levels of IGF-I (ng/ml) across increasing quartiles of milk intake were
183, 189, 188, and 200 (P = 0.01). Higher fat intake, in particular
saturated fat, was associated with lower levels of IGFBP-3. We conclude
that higher energy, protein, and milk intakes were associated with higher
levels of IGF-I. These associations raise the possibility that diet could
affect cancer risk through influencing IGF-I level.

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