Genetic mouse models of extended lifespan

Liang, Hanyu; Masoro, Edward J.; Nelson, James F.; Strong, Randy; McMahan, C. Alex; Richardson, Arlan

doi:10.1016/j.exger.2003.10.019

Cited by 209 publications

(163 citation statements)

References 69 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…The FGF21-Tg mice share other phenotypic similarities with long-lived dwarf mice including small size, reduced circulating insulin and IGF-1 concentrations, increased circulating adiponectin levels and female infertility. Like the Ames and Snell dwarf mice, female FGF21-Tg mice live longer than males (Liang et al, 2003; Brown-Borg and Bartke, 2012). These similarities together with our previous finding that FGF21-Tg mice are GH resistant (Inagaki et al, 2008) suggest that FGF21 may increase lifespan by inhibiting the GH/IGF-1 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Dwarf mice, including the pituitary loss-of-function Ames and Snell strains and GH receptor/GH binding protein-knockout mice, are the longest living mouse mutants discovered to date, living up to ∼70% longer than their wild-type counterparts (Liang et al, 2003; Bartke and Brown-Borg, 2004; Brown-Borg and Bartke, 2012). Interestingly, FGF21-Tg mice share a number of phenotypes with these long-lived mice including small size, enhanced insulin sensitivity and a blunted GH/IGF-1 signaling axis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

Zhang

Xie

Berglund

et al. 2012

eLife

332

252

View full text Add to dashboard Cite

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species.DOI: http://dx.doi.org/10.7554/eLife.00065.001

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

Zhang

Xie

Berglund

et al. 2012

eLife

332

252

View full text Add to dashboard Cite

show abstract

“…The demonstration that single gene mutations can have profound effects on the rates of ageing and lifespans of model organisms like C. elegans (Kenyon et al, 1993;Dorman et al, 1995;Ebert et al, 1996;Murakami and Johnson, 1996), Drosophila (Lin et al, 1998;Tatar et al, 2001;Clancy et al, 2001a;Aigaki et al, 2002Aigaki et al, , 2003 and the mouse (Migliacco et al, 1999;Bluher et al, 2003;Liang et al, 2003) has revolutionised our whole view of the phenomena of ageing and lifespan. Van Voorhies and Ward (1999) suggested that the differences in lifespans between daf-2 mutants and wild-type C. elegans could be entirely accounted for by differences in their rates of metabolism.…”

Section: (I) Studies Of Transgenic and Natural Mutant Animalsmentioning

confidence: 99%

“…Many other transgenic mice have been constructed with effects on lifespan (e.g. Migliaccio et al, 1999;Purdom and Chen, 2003;Liang et al, 2003;Bluher et al, 2003;Trifunovic et al, 2004), but in all these cases detailed measurements of energy metabolism are lacking. Oklejewicz et al (1997) measured the energy demands of Tau mutant Syrian hamsters Mesocricetus auratus.…”

Section: (I) Studies Of Transgenic and Natural Mutant Animalsmentioning

confidence: 99%

Body size, energy metabolism and lifespan

Speakman

2005

Journal of Experimental Biology

708

614

View full text Add to dashboard Cite

Bigger animals live longer. The scaling exponent for the relationship between lifespan and body mass is between 0.15 and 0.3. Bigger animals also expend more energy, and the scaling exponent for the relationship of resting metabolic rate (RMR) to body mass lies somewhere between 0.66 and 0.8. Mass-specific RMR therefore scales with a corresponding exponent between -0.2 and -0.33. Because the exponents for mass-specific RMR are close to the exponents for lifespan, but have opposite signs, their product (the mass-specific expenditure of energy per lifespan) is independent of body mass (exponent between -0.08 and 0.08). This means that across species a gram of tissue on average expends about the same amount of energy before it dies regardless of whether that tissue is located in a shrew, a cow, an elephant or a whale. This fact led to the notion that ageing and lifespan are processes regulated by energy metabolism rates and that elevating metabolism will be associated with premature mortalitythe rate of living theory.The free-radical theory of ageing provides a potential mechanism that links metabolism to ageing phenomena, since oxygen free radicals are formed as a by-product of oxidative phosphorylation. Despite this potential synergy in these theoretical approaches, the free-radical theory has grown in stature while the rate of living theory has fallen into disrepute. This is primarily because comparisons made across classes (for example, between birds and mammals) do not conform to the expectations, and even within classes there is substantial interspecific variability in the mass-specific expenditure of energy per lifespan. Using interspecific data to test the rate of living hypothesis is, however, confused by several major problems. For example, appeals that the resultant lifetime expenditure of energy per gram of tissue is 'too variable' depend on the biological significance rather than the statistical significance of the variation observed. Moreover, maximum lifespan is not a good marker of ageing and RMR is not a good measure of total energy metabolism. Analysis of residual lifespan against residual RMR reveals no significant relationship. However, this is still based on RMR.A novel comparison using daily energy expenditure (DEE), rather than BMR, suggests that lifetime expenditure of energy per gram of tissue is NOT independent of body mass, and that tissue in smaller animals expends more energy before expiring than tissue in larger animals. Some of the residual variation in this relationship in mammals is explained by ambient temperature. In addition there is a significant negative relationship between residual lifespan and residual daily energy expenditure in mammals. A potentially much better model to explore the links of body size, metabolism and ageing is to examine the intraspecific links. These studies have generated some data that support the original rate of living theory and other data that conflict. In particular several studies have shown that manipulating animals to expend more or less energy ...

show abstract

“…This is not the first time a study was unable to replicate the increase in lifespan shown in an original study. For example, knockout mouse models for the signaling molecule p66Shc (p66shc −/− mice) (Migliaccio et al., 1999), insulin receptor substrate 2 (Irs2) (Irs2 +/− mice) (Taguchi, Wartschow & White, 2007), and the IGF1 receptor ( Igf1r +/− mice) (Holzenberger et al., 2003) all showed substantial lifespan extension in initial reports that was not confirmed in follow‐up studies (Bokov et al., 2011; Ladiges et al., 2009; Liang et al., 2003 ; Ramsey et al., 2014; Selman, Lingard, Gems, Partridge & Withers, 2008; Selman et al., 2007; Unnikrishnan, Deepa, Herd & Richardson, 2017). Differences in genetic background can potentially modulate lifespan results.…”

Section: Discussionmentioning

confidence: 99%

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

et al. 2018

Self Cite

View full text Add to dashboard Cite

SummaryLoss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.

show abstract

Genetic mouse models of extended lifespan

Cited by 209 publications

References 69 publications

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

Body size, energy metabolism and lifespan

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

Contact Info

Product

Resources

About