IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.

Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-ß/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health.

Lamin A to Z in normal aging.

Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging. Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.

The Autophagy Inducer Spermidine Protects Against Metabolic Dysfunction During Overnutrition.

Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends life span across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in life-span extension in wild-type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts high-fat diet (HFD)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine fibroblast growth factor 21 (FGF21) expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21-/- mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy-deficient (Beclin-1flox/+Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occur through systemic changes in metabolism, involving multiple mechanistic pathways.

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.

Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.

Application of Atmospheric-Pressure-Plasma-Jet Modified Flexible Graphite Sheets in Reduced-Graphene-Oxide/Polyaniline Supercapacitors.

In this study, flexible and low-cost graphite sheets modified by atmospheric pressure plasma jet are applied to reduced-graphene-oxide/polyaniline supercapacitors. Surface treatment by atmospheric pressure plasma jet can make the hydrophobic surface of graphite into a hydrophilic surface and improve the adhesion of the screen-printed reduced-graphene-oxide/polyaniline on the graphite sheets. After the fabrication of reduced-graphene-oxide/polyaniline supercapacitors with polyvinyl alcohol/H2SO4 gel electrolyte, pseudo-capacitance and electrical double capacitance can be clearly identified by the measurement of cyclic voltammetry. The fabricated supercapacitor exhibits specific capacitance value of 227.32 F/g and areal capacitance value of 28.37 mF/cm2 with a potential scan rate of 2 mV/s. Meanwhile, the capacitance retention rate can reach 86.9% after 1000-cycle cyclic voltammetry test. A light-emitting diode can be lit by the fabricated reduced-graphene-oxide/polyaniline supercapacitors, which confirms that the supercapacitors function well and can potentially be used in a circuit.

Mechanistic target of rapamycin signaling in mouse models of accelerated aging.

The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.

MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.

Aging is accompanied by altered intercellular communication, deregulated metabolic function, and inflammation. Interventions that restore a youthful state delay or reverse these processes, prompting the search for systemic regulators of metabolic and immune homeostasis. Here we identify MANF, a secreted stress-response protein with immune modulatory properties, as an evolutionarily conserved regulator of systemic and in particular liver metabolic homeostasis. We show that MANF levels decline with age in flies, mice and humans, and MANF overexpression extends lifespan in flies. MANF deficient flies exhibit enhanced inflammation and shorter lifespans, and MANF heterozygous mice exhibit inflammatory phenotypes in various tissues, as well as progressive liver damage, fibrosis, and steatosis. We show that immune cell-derived MANF protects against liver inflammation and fibrosis, while hepatocyte-derived MANF prevents hepatosteatosis. Liver rejuvenation by heterochronic parabiosis in mice further depends on MANF, while MANF supplementation ameliorates several hallmarks of liver aging, prevents hepatosteatosis induced by diet, and improves age-related metabolic dysfunction. Our findings identify MANF as a systemic regulator of homeostasis in young animals, suggesting a therapeutic application for MANF in age-related metabolic diseases.

A novel rapamycin analog is highly selective for mTORC1 in vivo.

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.

Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weakness.

Physiological and premature aging are frequently associated with an accumulation of prelamin A, a precursor of lamin A, in the nuclear envelope of various cell types. Here, we aimed to underpin the hitherto unknown mechanisms by which prelamin A alters myonuclear organization and muscle fiber function. By experimentally studying membrane-permeabilized myofibers from various transgenic mouse lines, our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

Cinnamomum Cassia Extracts Suppress Human Lung Cancer Cells Invasion by Reducing u-PA/MMP Expression through the FAK to ERK Pathways.

Cinnamomum cassia exhibits antioxidative, apoptotic, and cytostatic properties. These activities have been attributed to the modulation of several biological processes and are beneficial for possible pharmaceutical applications. However, the potential of C. cassia in retarding lung adenocarcinoma cells metastasis remains ambiguous. We determined whether C. cassia extract (CCE) reduces metastasis of human lung adenocarcinoma cells. The results showed that CCE treatment (up to 60 µg/mL) for 24 h exhibited no cytotoxicity on the A549 and H1299 cell lines but inhibited the motility, invasiveness, and migration of these cells by repressing matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA). CCE also impaired cell adhesion to collagen. CCE significantly reduced p-focal adhesion kinase (FAK) Tyr397, p-FAK Tyr925, p-extracellular signal-regulated kinases (ERK)1/2, and Ras homolog gene family (Rho)A expression. CCE showed anti-metastatic activity of A549 and H1299 cells by repressing u-PA/MMP-2 via FAK to ERK1/2 pathways. These findings may facilitate future clinical trials of lung adenocarcinoma chemotherapy to confirm the promising results.

Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins.

The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are Lmna-/- mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in Lmna-/- mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in Lmna-/- mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for S6K1 ubiquitously extended lifespan of Lmna-/- mice (Lmna-/-S6K1+/- mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of S6K1 specifically in muscle tissue also extended survival of Lmna-/- mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of Lmna-/- mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in Lmna-/- mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.

Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice.

The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna-/- mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with increased body weight and fat content, two phenotypes we link to suppression of elevated energy expenditure. In both white and brown adipose tissue of Lmna-/- mice, we find that rapamycin inhibits mTORC1 but not mTORC2, leading to suppression of elevated lipolysis and restoration of thermogenic protein UCP1 levels, respectively. The short lifespan and metabolic phenotypes of Lmna-/- mice can be partially rescued by maintaining mice at thermoneutrality. Together, our findings indicate that altered mTOR signaling in Lmna-/- mice leads to a lipodystrophic phenotype that can be rescued with rapamycin, highlighting the effect of loss of adipose tissue in Lmna-/- mice and the consequences of altered mTOR signaling.

C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension.

Deficiency of S6 kinase (S6K) extends the lifespan of multiple species, but the underlying mechanisms are unclear. To discover potential effectors of S6K-mediated longevity, we performed a proteomics analysis of long-lived rsks-1/S6K C. elegans mutants compared to wild-type animals. We identified the arginine kinase ARGK-1 as the most significantly enriched protein in rsks-1/S6K mutants. ARGK-1 is an ortholog of mammalian creatine kinase, which maintains cellular ATP levels. We found that argk-1 is possibly a selective effector of rsks-1/S6K-mediated longevity and that overexpression of ARGK-1 extends C. elegans lifespan, in part by activating the energy sensor AAK-2/AMPK. argk-1 is also required for the reduced body size and increased stress resistance observed in rsks-1/S6K mutants. Finally, creatine kinase levels are increased in the brains of S6K1 knockout mice. Our study identifies ARGK-1 as a longevity effector in C. elegans with reduced RSKS-1/S6K levels.

SIRT6, oxidative stress, and aging.

The role of oxidative stress in the aging process has been highly debated for decades and remains equivocal. A new study published in Cell Research reports a novel role for the aging-associated SIRT6 deacetylase in the control of oxidative homeostasis in human mesenchymal stem cells.

Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins.

The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin (mTOR) is of intense interest because of its likely relevance in cancer biology, aging, and other age-related diseases. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been attributed recently to mTORC2 inhibition. Here, we identify the expression level of different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key determinants for rapamycin-mediated inhibition of mTORC2. In support, enforced reduction of FKBP12 completely converts a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, and increased expression can enhance mTORC2 inhibition. Further reduction of FKBP12 in cell lines with already low FKBP12 levels completely blocks mTORC1 inhibition by rapamycin, indicating that relative FKBP12 levels are critical for both mTORC1 and mTORC2 inhibition, but at different levels. In contrast, reduction of FKBP51 renders cells more sensitive to mTORC2 inhibition. Our findings reveal that the expression of FKBP12 and FKBP51 is the rate limiting factor that determines the responsiveness of a cell line or tissue to rapamycin. These findings have implications for treating specific diseases, including neurodegeneration and cancer, as well as targeting aging in general.

Mouse models and aging: longevity and progeria.

Aging is a complex, multifactorial process that is likely influenced by the activities of a range of biological pathways. Genetic approaches to identify genes modulating longevity have been highly successful and recent efforts have extended these studies to mammalian aging. A variety of genetic models have been reported to have enhanced lifespan and, similarly, many genetic interventions lead to progeroid phenotypes. Here, we detail and evaluate both sets of models, focusing on the insights they provide about the molecular processes modulating aging and the extent to which mutations conferring progeroid pathologies really phenocopy accelerated aging.

Genetic variation in responses to dietary restriction--an unbiased tool for hypothesis testing.

Dietary restriction (DR) extends lifespan in a wide range of animal models. A major obstacle to understanding how DR modulates lifespan and aging-related dysfunction is the multiplicity of physiological and molecular changes associated with DR. Unraveling their importance to the longevity effect of DR remains a major challenge. In this perspective, we review the marked genetic variation in the response to DR of multiple recombinant inbred (RI) mouse strains. We illustrate how this genetic variation can be exploited to probe the mechanisms mediating lifespan extension by DR, as well as uncover its limits as an intervention. RI strains exhibit marked variation in their lifespan as well as physiological responses to DR. Quantitative genetic and statistical tools can use this phenotypic variation to probe the importance of physiological and molecular changes that have been hypothesized to play roles in DR-mediated lifespan extension.

Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival.

Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors.

Will the real aging Sirtuin please stand up?

Initial studies linking Sirtuins to longevity in yeast initiated what is now a rich vein of aging research that is full of promise and fraught with controversy. Missing was a demonstration that enhanced Sirtuin expression extends lifespan in mammals. Now Kanfi et al. provide the evidence but with an interesting plot twist - the lesser known SIRT6 is the longevity factor.