Fat maintenance is a predictor of the murine lifespan response to dietary restriction

“The case favoring a role for reduced fat is based on the role of excess visceral adiposity in insulin resistance, type II diabetes, and metabolic syndrome (Despres & Lemieux, 2006).”

“For example, DR increases the plasma level of adiponectin, which is secreted exclusively from adipose tissue and is involved in glucose homeostasis and insulin sensitivity (Berg et al., 2001; Zhu et al., 2004).”

“The life-extending effect of dietary restriction (DR) has long been known (McCay et al., 1935; Weindruch & Walford, 1988), but the underlying molecular and physiological mechanisms are still obscure (Masoro, 2005).”

“Given the different effects of subcutaneous, visceral, and brown fat on metabolic function (Rosen & Spiegelman, 2006; Tran et al., 2008), it will be informative to determine (i) whether the inverse relationship between fat and lifespan modulation holds for all or only selected fat depots and (ii)…”

“Epidemiologic studies show that both too much or too little fat are deleterious for lifespan (Flegal et al., 2007; Orpana et al., 2010) – a result that produces an inverted U-shaped curve for the relationship between adiposity and longevity.”

“…that do not exhibit metabolic disease or obesity (Masoro et al., 1992; McCarter et al., 2007) nor the beneficial effects of DR on pathological conditions and age-related dysfunctions (e.g., lymphoma and cataracts) not primarily linked to metabolic disease or obesity (Weindruch & Walford, 1988).”

“The phenotypic data (the mean of each strain and group) were subjected to a QTL mapping using Map Manager QTXb20 (Manly et al., 2001).”

“DR also decreases tumor necrosis factor-a (TNF-a) from adipose tissue, which impairs insulin signaling and thereby increases insulin resistance (Barzilai & Gupta, 1999; Bordone & Guarente, 2005).”

“Also, positive correlations have been observed in DR mice between lifespan and body weight (BW) (Weindruch et al., 1986; Goodrick et al., 1990; Harper et al., 2006; Rikke et al., 2010).”

“…namely reductions in body temperature, metabolic rate, and motor activity (Waterlow, 1986) – especially because the first two responses have been implicated as potential anti-aging mechanisms in DR (Rikke & Johnson, 2004, 2007; Conti et al., 2006; Ferguson et al., 2008) (reviewed by Masoro, 2005).”

“…Society of Great Britain and Ireland 629 Aging Cell (2011) 10, pp629–639 Doi: 10.1111/j.1474-9726.2011.00702.x Ag in g Ce ll information, which facilitates finding genes that underlie quantitative traits (Flint & Mott, 2001; Glazier et al., 2002; Korstanje & Paigen, 2002; Flint et al., 2005).”

“Given the different effects of subcutaneous, visceral, and brown fat on metabolic function (Rosen & Spiegelman, 2006; Tran et al., 2008), it will be informative to determine (i) whether the inverse relationship between fat and lifespan modulation holds for all or only selected fat depots and (ii) whether strains in wh…”

“The lifespan data are from Liao et al. (2010a).”

“information, which facilitates finding genes that underlie quantitative traits (Flint & Mott, 2001; Glazier et al., 2002; Korstanje & Paigen, 2002; Flint et al., 2005).”

“…Society of Great Britain and Ireland 629 Aging Cell (2011) 10, pp629–639 Doi: 10.1111/j.1474-9726.2011.00702.x Ag in g Ce ll information, which facilitates finding genes that underlie quantitative traits (Flint & Mott, 2001; Glazier et al., 2002; Korstanje & Paigen, 2002; Flint et al., 2005).”

“However, several studies have reported that resting metabolic rate normalized to lean body mass is not decreased by DR after the initial period of body mass adjustment to reduced caloric intake (McCarter & Palmer, 1992; Hambly & Speakman, 2005).”

“Also, positive correlations have been observed in DR mice between lifespan and body weight (BW) (Weindruch et al., 1986; Goodrick et al., 1990; Harper et al., 2006; Rikke et al., 2010).”

“Furthermore, removal of visceral fat not only improves insulin sensitivity (Barzilai et al., 1998; Das et al., 2004) but also extends the lifespan of one strain of rat (Muzumdar et al.”

“This machine utilizes nuclear magnetic resonance (NMR) to reliably and accurately analyze the physical state of the tissue (Taicher et al., 2003; Tinsley et al., 2004), which provides an estimate of total body fat, lean mass, and free water.”

“This machine utilizes nuclear magnetic resonance (NMR) to reliably and accurately analyze the physical state of the tissue (Taicher et al., 2003; Tinsley et al., 2004), which provides an estimate of total body fat, lean mass, and free water.”

“…Society of Great Britain and Ireland 629 Aging Cell (2011) 10, pp629–639 Doi: 10.1111/j.1474-9726.2011.00702.x Ag in g Ce ll information, which facilitates finding genes that underlie quantitative traits (Flint & Mott, 2001; Glazier et al., 2002; Korstanje & Paigen, 2002; Flint et al., 2005).”

“Epidemiologic studies show that both too much or too little fat are deleterious for lifespan (Flegal et al., 2007; Orpana et al., 2010) – a result that produces an inverted U-shaped curve for the relationship between adiposity and longevity.”

“Furthermore, removal of visceral fat not only improves insulin sensitivity (Barzilai et al., 1998; Das et al., 2004) but also extends the lifespan of one strain of rat (Muzumdar et al., 2008).”

“Also, positive correlations have been observed in DR mice between lifespan and body weight (BW) (Weindruch et al., 1986; Goodrick et al., 1990; Harper et al., 2006; Rikke et al., 2010).”

“…energy expenditure and preserve fat mass during nutrient deprivation, namely reductions in body temperature, metabolic rate, and motor activity (Waterlow, 1986) – especially because the first two responses have been implicated as potential anti-aging mechanisms in DR (Rikke & Johnson, 2004,…”

“However, several studies have reported that resting metabolic rate normalized to lean body mass is not decreased by DR after the initial period of body mass adjustment to reduced caloric intake (McCarter & Palmer, 1992; Hambly & Speakman, 2005).”

“Although absolute fat mass and life extension were positively correlated in one strain of rat under DR (Bertrand et al., 1980), no study has asked whether fat reduction per se is associated”

“In addition, the lifespan of genetically obese mice (ob ⁄ ob) under DR was found to be the same as the lifespan of their wild-type littermates under DR, even though the obese mice on DR had much higher levels of fat than their wild-type ad libitum (AL) controls (Harrison et al., 1984).”

“For example, DR increases the plasma level of adiponectin, which is secreted exclusively from adipose tissue and is involved in glucose homeostasis and insulin sensitivity (Berg et al., 2001; Zhu et al., 2004).”

“Although obesity is strongly associated with hyperglycemia and insulin resistance, lipoatrophy, a condition of depleted fat reserves, is also a risk factor – not only for insulin resistance (Reitman et al., 1999) but also for elevated inflammatory tone (Herrero et al., 2010).”

“However, the absence of significant QTLs affecting lifespan indicates that the QTL effect sizes for longevity are below our limit of reliable detection; in this study, a QTL would have to explain 43% of the genetic variation to be detected with 80% power (Belknap et al., 1996).”

“Although a large number of QTLs and potential genes have been identified for BW, body composition, and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study…”

“These findings also contradict a simple model in which lower temperature per se (independent of lower metabolic rate) extends lifespan (Turturro & Hart, 1991; Koizumi et al., 1992; Rikke & Johnson, 2004; Conti et al., 2006; Conti, 2008).”

“Reduction in fat mass has been argued to be a key factor (Barzilai, 1999; Barzilai & Gupta, 1999; Masoro, 1999; Barzilai & Gabriely, 2001; Das et al., 2004).”

“…runwheel activity, by about 50% when fed 60% AL, with only Fat, longevity, and dietary restriction, C.-Y. Liao et al. ª 2011 The Authors Aging Cell ª 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 635 one strain of 14 showing increased activity (Rikke et al., 2003).”

“To test the hypothesis that fat reduction under DR is important for life extension, we measured the response of fat and lean mass in the ILSXISS RI mouse strains (Williams et al., 2004): 38 strains for males and 33 for females.”

“Reduced motor activity is another adaptive response to conserve energy and preserve fat (Hambly & Speakman, 2005).”

“Reduction in fat mass has been argued to be a key factor (Barzilai, 1999; Barzilai & Gupta, 1999; Masoro, 1999; Barzilai & Gabriely, 2001; Das et al., 2004).”

“Interestingly, DR in C57BL ⁄ 6J females redistributed fat stores in favor of subcutaneous depots over visceral (Varady et al., 2010); a limitation of our study is that fat depots were not distinguishable by our measurement technique.”

“DR rats have reduced plasma thyroid hormone (Herlihy et al., 1990), a hormonal response”

“The suggestive QTLs on chromosome is overlap with and provide further validation of the QTL that we identified previously as affecting fuel efficiency in response to DR (Rikke et al., 2010), the inbred long-sleep (ILS)”

“…AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has searched for genetic loci modulating adiposity and lean mass under DR. Earlier studies using ILSXISS RI mouse…”

“Although obesity is strongly associated with hyperglycemia and insulin resistance, lipoatrophy, a condition of depleted fat reserves, is also a risk factor – not only for insulin resistance (Reitman et al., 1999) but also for elevated inflammatory tone (Herrero et al., 2010).”

“These findings also contradict a simple model in which lower temperature per se (independent of lower metabolic rate) extends lifespan (Turturro & Hart, 1991; Koizumi et al., 1992; Rikke & Johnson, 2004; Conti et al., 2006; Conti, 2008).”

“Another energy-conserving response to reduced food availability is a reduction in lean body mass, which reduces whole animal metabolic rate (Hambly & Speakman, 2005; Li et al., 2010).”

“…namely reductions in body temperature, metabolic rate, and motor activity (Waterlow, 1986) – especially because the first two responses have been implicated as potential anti-aging mechanisms in DR (Rikke & Johnson, 2004, 2007; Conti et al., 2006; Ferguson et al., 2008) (reviewed by Masoro, 2005).”

“…for BW, body composition, and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has searched for genetic loci modulating adiposity and lean mass…”

“…genes have been identified for BW, body composition, and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has searched for genetic loci modulating…”

“…a large number of QTLs and potential genes have been identified for BW, body composition, and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has…”

“These findings also contradict a simple model in which lower temperature per se (independent of lower metabolic rate) extends lifespan (Turturro & Hart, 1991; Koizumi et al., 1992; Rikke & Johnson, 2004; Conti et al., 2006; Conti, 2008).”

“, 2008), this view does not account for DRinduced lifespan extension in strains that do not exhibit metabolic disease or obesity (Masoro et al., 1992; McCarter et al., 2007) nor the beneficial effects of DR on pathological conditions and age-related dysfunctions (e.”

“Although a large number of QTLs and potential genes have been identified for BW, body composition, and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has searched for gen…”

“This study used 41 ILSXISS RI mouse strains (Williams et al., 2004) (formerly called LXS) originally developed to analyze genetic variation in alcohol sensitivity (Bennett et al., 2006).”

“0001, one-way ANOVA) as reported previously at earlier ages (Rikke et al., 2006).”

“…of this relationship is remarkable given that the body temperature and body composition responses to DR were measured in separate cohorts and colonies, and surprising given that the body temperature and BW responses to DR were not correlated when measured in the same cohort (Rikke & Johnson, 2007).”

“To determine whether fat and lean mass were heritable and thus suitable for linkage analysis, the heritability (h2RI, narrow sense) was calculated as previously described (Rikke et al., 2004).”

“…and lifespan under AL feeding (Gelman et al., 1988; de Haan et al., 1998; Miller et al., 1998; Jackson et al., 2002; Henckaerts et al., 2004; de Haan & Williams, 2005; Wuschke et al., 2007), no study has searched for genetic loci modulating adiposity and lean mass under DR. Earlier studies…”

“The lifespan data are from Liao et al. (2010a).”

“Reduction in fat mass has been argued to be a key factor (Barzilai, 1999; Barzilai & Gupta, 1999; Masoro, 1999; Barzilai & Gabriely, 2001; Das et al., 2004).”

“Reduction in fat mass has been argued to be a key factor (Barzilai, 1999; Barzilai & Gupta, 1999; Masoro, 1999; Barzilai & Gabriely, 2001; Das et al., 2004).”

“These findings also contradict a simple model in which lower temperature per se (independent of lower metabolic rate) extends lifespan (Turturro & Hart, 1991; Koizumi et al., 1992; Rikke & Johnson, 2004; Conti et al., 2006; Conti, 2008).”

“The strains with lower Tb under CR had less fat (Liao et al., 2011).”

“It is possible that the preservation of fat mass in CR mice between 12 and 24 months of age plays a protective role in survival and lifespan extension, in agreement with previous findings (Liao et al., 2011).”