Growth signaling and longevity in mouse models

Kim, Seung Soo; Lee, Cheol Koo

doi:10.5483/bmbrep.2019.52.1.299

Cited by 15 publications

(10 citation statements)

References 114 publications

(168 reference statements)

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“…However, unlike NlInR1 RNAi , NlInR2 -null mutants had marginal effects on fuel metabolism, lifespan, and decreased starvation tolerance. This observation stands in sharp contrast to the extended longevity of InR mutants in major model organisms, including worms [ 15 ], flies [ 19 ], and mice [ 56 ]. Although the exact mechanisms are unknown, this phenotypic feature in NlInR2 mutants may challenge the evolutionarily conserved roles of InR in fuel metabolism and longevity.…”

Section: Discussionmentioning

confidence: 91%

Neofunctionalization of a second insulin receptor gene in the wing-dimorphic planthopper, Nilaparvata lugens

Xue

Chen

et al. 2021

PLoS Genet

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A single insulin receptor (InR) gene has been identified and extensively studied in model species ranging from nematodes to mice. However, most insects possess additional copies of InR, yet the functional significance, if any, of alternate InRs is unknown. Here, we used the wing-dimorphic brown planthopper (BPH) as a model system to query the role of a second InR copy in insects. NlInR2 resembled the BPH InR homologue (NlInR1) in terms of nymph development and reproduction, but revealed distinct regulatory roles in fuel metabolism, lifespan, and starvation tolerance. Unlike a lethal phenotype derived from NlInR1 null, homozygous NlInR2 null mutants were viable and accelerated DNA replication and cell proliferation in wing cells, thus redirecting short-winged–destined BPHs to develop into long-winged morphs. Additionally, the proper expression of NlInR2 was needed to maintain symmetric vein patterning in wings. Our findings provide the first direct evidence for the regulatory complexity of the two InR paralogues in insects, implying the functionally independent evolution of multiple InRs in invertebrates.

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Section: Discussionmentioning

confidence: 91%

Neofunctionalization of a second insulin receptor gene in the wing-dimorphic planthopper, Nilaparvata lugens

Xue

Chen

et al. 2021

PLoS Genet

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“…Studies in nonvertebrate model systems such as the nematode Caenorhabditis elegans or the fruit fly Drosophila melanogaster find that moderate to high insulin activity shortens lifespan [57,58]. A consistent finding from mouse model studies is that decreased signaling of anabolic hormones like insulin, insulin-like growth factor, or growth hormone results in a prolonged lifespan [59]. Disruption of the insulin-receptor substrate 1 gene caused insulin-resistance with defects in insulin signaling [60] and led to an extension of lifespan by 14-16% [61].…”

Section: Chronically Elevated Insulin Concentrations Impair Body Funcmentioning

confidence: 89%

Insulin: too much of a good thing is bad

Kolb

Kempf

Röhling

et al. 2020

BMC Med

116

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Background: Insulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions. Main body: The physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production. Conclusions: The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.

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“…Indeed, bats have physiologic (e.g., pancreatic structure) and transcriptomic changes that resemble growth hormone receptor knockout mice (Liu et al, 2004;Seim et al, 2013;Swindell, 2007). There are also intriguing changes in the transmembrane region of the IGF1 receptor, which is associated with longevity in a range of model organisms and in centenarians (Kim and Lee, 2019;Seim et al, 2013). Both of these hormonal signaling pathways are intimately linked to nutrient signaling, one of the most robust pillars of aging (Figure 3).…”

Section: Longevity Adaptationsmentioning

confidence: 99%