Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids

Miller, Karl; Burhans, Maggie S.; Clark, Josef P.; Howell, Porsha R.; Polewski, Michael A.; DeMuth, Tyler M.; Eliceiri, Kevin W.; Lindstrom, Mary J.; Ntambi, James M.; Anderson, Rozalyn M.

doi:10.1111/acel.12575

Cited by 105 publications

(91 citation statements)

References 47 publications

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“…Most fatty acids measured are increased by the KD relative to the control diet, consistent with the KD consisting of 90% fat (Extended Data Table 1). In contrast, levels of almost all fatty acids are reduced by CR, particularly in the TIF, which is consistent with previous studies showing how CR can decrease circulating lipid levels [29][30][31][32][33] . This observation suggests that compared to the KD, decreased systemic availability of lipids and fatty acids to the tumor is specific to CR, and environmental lipid limitation could be one metabolic mechanism by which CR inhibits tumor growth.…”

supporting

confidence: 92%

Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition

Lien

Westermark

et al. 2020

Preprint

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Dietary interventions can change metabolite levels in the tumor microenvironment,which may then affect cancer cell metabolism to alter tumor growth 1-6 . Although caloric restriction (CR) and the ketogenic diet (KD) are often thought to inhibit tumor growth through lowering blood glucose and insulin levels 7-12 , only CR inhibits the growth of pancreatic ductal adenocarcinoma allografts in mice, demonstrating that this diet can limit tumor growth in other ways. A change in nutrient availability observed with CR, but not the KD, that can contribute to tumor growth inhibition is lower lipid levels in the plasma and in tumor interstitial fluid. Limiting exogenous lipid availability to cultured cancer cells results in up-regulation of stearoyl-CoA desaturase (SCD), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. Fatty acid desaturation is required to dispose of toxic saturated fatty acids, and not because monounsaturated fatty acids are specifically needed for proliferation. Surprisingly, CR also inhibits tumor SCD activity, and enforced SCD expression confers resistance to the effects of CR. Therefore, CR both limits lipid availability and impairs tumor SCD activity, thereby limiting cancer cell adaptation to a diet-induced change in the tumor microenvironment that results in tumor growth inhibition.How diet affects cancer progression and survival is an important question for many cancer patients. While multiple studies have examined how different diets can influence both whole-body hormone signaling and cancer cell signaling processes 7,8,10,11,[13][14][15][16] , how dietary interventions might impact tumor growth by altering nutrient access to cancer cells in tumors is less studied. Consistent with the notion that the activities of various metabolic pathways in cancer cells can be strongly influenced by nutrient availability in the local environment 17-21 , dietary deprivation of specific amino acids can limit the growth of some tumors 2,4-6 . Whether Biotherapeutics, iTeos Therapeutics, and Auron Therapeutics. E.C.L., A.M.W., Z.L., and K.M.S. declare no competing interests.

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supporting

confidence: 92%

Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition

Lien

Westermark

et al. 2020

Preprint

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“…Relative levels of essential fatty acids 18:2n‐6 and 18:3n‐3 were higher in phosphatidylcholines and phosphatidylethanolamines from PGC‐OE compared to controls. The composition changes in cellular phospholipids in response to this modest increase in PGC‐1a are reminiscent of the changes in composition of circulating phospholipids induced by CR (Miller et al, ).…”

Section: Resultsmentioning

confidence: 90%

“…Fluorescence lifetime imaging microscopy (FLIM) measures the kinetics of photon release from endogenous pools of NADH and NADPH, informing of the microenvironment of the fluorophores. Fluorescence decay kinetics are characterized by a first‐order decay curve according to the formula: τ m = a 1 •τ 1 + a 2 •τ 2 , where the fast component (τ 1 ) corresponds to free, or unbound NAD(P)H and the slow component (τ 2 ) corresponds to protein‐bound NAD(P)H (Miller et al, ). The relative contribution of τ 1 to the decay curve is represented by the coefficient a 1 , effectively a measure of the percent of NAD(P)H in the free state.…”

Section: Resultsmentioning

confidence: 99%

PGC‐1a integrates a metabolism and growth network linked to caloric restriction

et al. 2019

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Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC‐1a is induced by CR in multiple tissues, and at the cellular level, CR‐like activation of PGC‐1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC‐1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post‐transcriptional and post‐translational mechanisms were also identified as outcomes of PGC‐1a‐directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC‐1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC‐1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.

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“…Mechanistically, we provide evidence that GDF11 acts directly on adipocytes to induce adiponectin secretion. Adiponectin regulates energy expenditure by acting directly in the brain to reduce weight without affecting appetite (Qi et al, ), and its levels are known to increase in the context of CR (Miller et al, ), suggesting that this hormone may have an important role in regulating systemic energy levels in the GDF11 paradigm. It is interesting to note that adiponectin was equally affected in both GDF11 and CR paradigms, lending credence to the idea that GDF11 mimics CR effects.…”

Section: Discussionmentioning

confidence: 99%

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

et al. 2019

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Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic GDF11 triggers a calorie restriction-like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, GDF11 could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders. K E Y W O R D Sadiponectin, aging, calorie restriction, GDF11, heterochronic parabiosis, rejuvenation | 9 of 11 KATSIMPARDI eT Al. GDF11 (Peprotech, was dissolved in water, further diluted according to the manufacturer's instructions, and injected at a concentration of 1 mg/kg. Control mice (young or aged) were injected with equivalent volumes of saline. Injection concentration was chosen based on a pilot study with three different concentrations (0.1, 0.5, and 1.0 mg/kg) where consistent weight loss and brain rejuvenation were observed upon 1 mg/kg GDF11 administration. The half-life of GDF11 at these concentrations was found to be of 12 hr. | GDF11 administration

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Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids

Cited by 105 publications

References 47 publications

Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition

Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition

PGC‐1a integrates a metabolism and growth network linked to caloric restriction

Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

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