Insulin Exposure and Aging Theory

Parr, Tyler

doi:10.1159/000213848

Cited by 38 publications

(26 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IGF-1 is a 70 amino acid polypeptide that shares~50% homology with insulin (9), while leptin is the product of the ob gene, which is known to regulate appetite and energy expenditure (27). Reductions in leptin and IGF-1 levels have been observed in other studies of early-onset CR (27,28). In addition, the enhancement of apoptosis and suppression of proliferation in altered hepatic foci in rats in response to short-term fasting has been associated with decreased liver IGF-1 mRNA expression (29).…”

Section: Discussionmentioning

confidence: 64%

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

Berrigan¹

2002

Carcinogenesis

185

114

View full text Add to dashboard Cite

Heterozygous p53-deficient (p53 ⍣/-) mice, a potential model for human Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and lymphoma; the median time to death of p53⍣/-mice is 18 months. We have shown previously that juvenileonset calorie restriction (CR) to 60% of ad libitum (AL) intake delays tumor development in young p53-null (-/-) mice by a p53-independent and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether CR is effective when started in adult p53-deficient mice, and to compare chronic CR with an intermittent fasting regimen, male p53⍣/-mice (7-10 months old, 31-32 mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on non-fasting days was controlled to prevent compensatory over feeding. Relative to the AL group, CR significantly delayed (P ⍧ 0.001) the onset of tumors in adult mice, whereas the 1 day/week fast caused a moderate delay (P ⍧ 0.039). Substantial variation in longevity and maximum body weight within treatments was not correlated with variation in growth characteristics of individual mice. In a separate group of p53⍣/-mice treated for 4 weeks (n ⍧ five mice per treatment), plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed carcinogenesis-even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage-support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention.

show abstract

Section: Discussionmentioning

confidence: 64%

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

Berrigan¹

2002

Carcinogenesis

185

114

View full text Add to dashboard Cite

show abstract

“…some data show that old CR mice retain better GH receptor function than old ad libitum-fed mice (604). A major mechanism may be via the lowering of nutritionally-driven insulin exposure which lowers overall growth factor exposure (605). One relatively clear finding in monkeys is that CR reduced body temperature, as a result of decreasing energy expenditure, consistent with the "rate of living" theory of aging (606).…”

Section: Caloric Restrictionmentioning

confidence: 85%

T cells and aging (update February 1999)

Pawelec

1999

Front Biosci

113

View full text Add to dashboard Cite

T cell immunosenescence 218effects of dysregulated immune responses in the elderly by supplementation or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. FACTORS CONTRIBUTING TO IMMUNO-SENESCENCE HematopoiesisDysregulated hematopoiesis is seen in elderly individuals, raising the possibility that this could contribute to altered immune function in the aged. Hematopoiesis in man may be compromised because of a severely reduced capacity to produce colony stimulating factors (44) and increased production of pro-inflammatory factors such as IL 6 (45), because lower numbers of progenitor cells are present in the BM (46) and because of an age-related decline in proliferative potential of putative haematopoietic stem cells (HSC) (47). In mice, the repopulating potential of murine fetal liver-derived HSC is higher than that of adult BM-derived stem cells (48), suggesting possible aging of the HSC themselves. Normal cells with shorter telomeres possess less remaining replicative capacity than those with longer telomeres (see section 5.2). Accordingly, HSC from adult BM were found to have shorter telomeres than fetal liver-derived or umbilical cord-derived stem cells, consistent with aging of HSC (49). Telomere lengths decreased on culture despite low level expression of telomerase in these cells (50,51), although the rate of basepair loss per population doubling of cells in culture was lower during the first two weeks, when telomerase was upregulated, than in the next two, when it was downregulated (52). The telomerase expressed is therefore functionally active but may not be able to completely maintain telomere length in aging HSC cells. True embryonic stem cells (ESC), on the other hand, which may really be immortal, do retain high levels of telomerase activity (53). On the other hand, ESC from telomerase-knockout mice show gradual telomere shortening over many population doublings (PD) resulting in slowing and eventual cessation of growth (54). Certain animals which do not downregulate telomerase manifest a permanent growth phase and little or no senescence (55,56).

show abstract

“…In Caenorhabditis elegans (C. elegans), it was shown that Nrf2 (SKN-1, a synonyms in C. elegans) can be directly phosphorylated by Akt, leading to the repression of its nuclear translocation [43] . Since oxidative stress is associated with aging and Akt/insulin signaling is a critical signaling that causes aging [44] , this repression may be among the mechanisms for insulin signaling in accelerating aging. However, in mammals, a number of studies have actually shown that insulin signaling is required for Nrf2 activation [45,46] .…”

Section: Role Of the Nrf2 System In Regulating Insulin Signaling And mentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Zhong

Li²,

Liu³

et al. 2012

WJD

View full text Add to dashboard Cite

Redox balance is fundamentally important for physiological homeostasis. Pathological factors that disturb this dedicated balance may result in oxidative stress, leading to the development or aggravation of a variety of diseases, including diabetes mellitus, cardiovascular diseases, metabolic syndrome as well as inflammation, aging and cancer. Thus, the capacity of endogenous free radical clearance can be of patho-physiological importance; in this regard, the major reactive oxygen species defense machinery, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system needs to be precisely modulated in response to pathological alterations. While oxidative stress is among the early events that lead to the development of insulin resistance, the activation of Nrf2 scavenging capacity leads to insulin sensitization. Furthermore, Nrf2 is evidently involved in regulating lipid metabolism. Here we summarize recent findings that link the Nrf2 system to metabolic homeostasis and insulin action and present our view that Nrf2 may serve as a novel drug target for diabetes and its complications.

show abstract

Insulin Exposure and Aging Theory

Cited by 38 publications

References 62 publications

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice

T cells and aging (update February 1999)

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Contact Info

Product

Resources

About