Aging, Lifespan & Longevity

Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.

Autophagy. 2021 Jan 19;:1-20

Authors: Wani A, Al Rihani SB, Sharma A, Weadick B, Govindarajan R, Khan SU, Sharma PR, Dogra A, Nandi U, Reddy CN, Bharate SS, Singh G, Bharate SB, Vishwakarma RA, Kaddoumi A, Kumar A

Abstract
Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aβ clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aβ levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.

PMID: 33404280 [PubMed - as supplied by publisher]

Base editor repairs mutation found in the premature-ageing syndrome progeria.

Nature. 2021 01;589(7843):522-524

Authors: Vermeij WP, Hoeijmakers JHJ

PMID: 33408358 [PubMed - indexed for MEDLINE]

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Nature. 2021 Jan;589(7843):608-614

Authors: Koblan LW, Erdos MR, Wilson C, Cabral WA, Levy JM, Xiong ZM, Tavarez UL, Davison LM, Gete YG, Mao X, Newby GA, Doherty SP, Narisu N, Sheng Q, Krilow C, Lin CY, Gordon LB, Cao K, Collins FS, Brown JD, Liu DR

Abstract
Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1-4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

PMID: 33408413 [PubMed - in process]

Gene therapy beats premature-aging syndrome in mice.

Science. 2021 01 08;371(6525):114

Authors: Kaiser J

PMID: 33414202 [PubMed - indexed for MEDLINE]

Brain changes associated with sleep disruption in cognitively unimpaired older adults: a short review of neuroimaging studies.

Ageing Res Rev. 2021 Jan 05;:101252

Authors: André C, Laniepce A, Chételat G, Rauchs G

Abstract
Ageing is characterized by a progressive decline of sleep quality. Sleep difficulties are increasingly recognized as a risk factor for Alzheimer's disease (AD), and have been associated with cognitive decline. However, the brain substrates underlying this association remain unclear. In this review, our objective was to provide a comprehensive overview of the relationships between sleep changes and brain structural, functional and molecular integrity, including amyloid and tau pathologies in cognitively unimpaired older adults. We especially discuss the topography and causality of these associations, as well as the potential underlying mechanisms. Taken together, current findings converge to a link between several sleep parameters, amyloid and tau levels in the CSF, and neurodegeneration in diffuse frontal, temporal and parietal areas. However, the existing literature remains heterogeneous, and the specific sleep changes associated with early AD pathological changes, in terms of topography and neuroimaging modality, is not clearly established yet. Notably, if slow wave sleep disruption seems to be related to frontal amyloid deposition, the brain correlates of sleep-disordered breathing and REM sleep disruption remains unclear. Moreover, sleep parameters associated with tau- and FDG-PET imaging are largely unexplored. Lastly, whether sleep disruption is a cause or a consequence of brain alterations remains an open question.

PMID: 33418092 [PubMed - as supplied by publisher]

Constructing multifunctional solid electrolyte interface via in-situ polymerization for dendrite-free and low N/P ratio lithium metal batteries.

Nat Commun. 2021 Jan 08;12(1):186

Authors: Luo D, Zheng L, Zhang Z, Li M, Chen Z, Cui R, Shen Y, Li G, Feng R, Zhang S, Jiang G, Chen L, Yu A, Wang X

Abstract
Stable solid electrolyte interface (SEI) is highly sought after for lithium metal batteries (LMB) owing to its efficient electrolyte consumption suppression and Li dendrite growth inhibition. However, current design strategies can hardly endow a multifunctional SEI formation due to the non-uniform, low flexible film formation and limited capability to alter Li nucleation/growth orientation, which results in unconstrained dendrite growth and short cycling stability. Herein, we present a novel strategy to employ electrolyte additives containing catechol and acrylic groups to construct a stable multifunctional SEI by in-situ anionic polymerization. This self-smoothing and robust SEI offers multiple sites for Li adsorption and steric repulsion to constrain nucleation/growth process, leading to homogenized Li nanosphere formation. This isotropic nanosphere offers non-preferred Li growth orientation, rendering uniform Li deposition to achieve a dendrite-free anode. Attributed to these superiorities, a remarkable cycling performance can be obtained, i.e., high current density up to 10 mA cm-2, ultra-long cycle life over 8500 hrs operation, high cumulative capacity over 4.25 Ah cm-2 and stable cycling under 60 °C. A prolonged lifespan can also be achieved in Li-S and Li-LiFePO4 cells under lean electrolyte content, low N/P ratio or high temperature conditions. This facile strategy also promotes the practical application of LMB and enlightens the SEI design in related fields.

PMID: 33420036 [PubMed]

Large-area and efficient perovskite light-emitting diodes via low-temperature blade-coating.

Nat Commun. 2021 Jan 08;12(1):147

Authors: Chu S, Chen W, Fang Z, Xiao X, Liu Y, Chen J, Huang J, Xiao Z

Abstract
Large-area light-emitting diodes (LEDs) fabricated by mass-production techniques are needed for low-cost flat-panel lighting. Nevertheless, it is still challenging to fabricate efficient large-area LEDs using organic small molecules (OLEDs), quantum dots (QLEDs), polymers (PLEDs), and recently-developed hybrid perovskites (PeLEDs) due to difficulties controlling film uniformity. To that end, we report sol-gel engineering of low-temperature blade-coated methylammonium lead iodide (MAPbI3) perovskite films. The precipitation, gelation, aging, and phase transformation stages are dramatically shortened by using a diluted, organoammonium-excessed precursor, resulting in ultra-flat large-area films (54 cm2) with roughness reaching 1 nm. The external quantum efficiency of doctor-bladed PeLEDs reaches 16.1%, higher than that of best-performing blade-coated OLEDs, QLEDs, and PLEDs. Furthermore, benefitting from the throughput of the blade-coating process and cheap materials, the expected cost of the emissive layer is projected to be as low as 0.02 cents per cm2, emphasizing its application potential.

PMID: 33420040 [PubMed]

Potentially modifiable risk factors for slow gait in community-dwelling older adults: A systematic review.

Ageing Res Rev. 2021 Jan 08;66:101253

Authors: Figgins E, Pieruccini-Faria F, Speechley M, Montero-Odasso M

Abstract
PURPOSE: Slow gait speed in older adults is associated with increased risk for falls and fractures, functional dependence, multimorbidity, and even mortality. The risk of these adverse outcomes can be reduced by intervening on potentially modifiable risk factors. The purpose of this systematic review was to identify potentially modifiable risk factors associated with slow gait speed and clinically meaningful gait speed decline in older community-dwelling adults.
METHODS: Literature searches were conducted in MEDLINE, EMBASE, and CINAHL, Google Scholar, and in the bibliographies of retrieved articles.
RESULTS: Forty studies met the inclusion criteria for qualitative review. Study designs were cross-sectional and longitudinal. Operational definitions of 'slow gait' and 'meaningful gait speed decline' were variable and based on sample distributions (e.g. quartiles), external criteria (e.g. < 0.8 m/s), and dynamic changes over time (e.g. ≥ 0.05 m/s decline per year). Twenty-six potentially modifiable risk factors were assessed in at least two studies. The risk factors most commonly investigated and that showed significant associations with slow gait and/or meaningful gait speed decline include physical activity, education, body mass index-obesity, pain, and depression/depressive symptoms.
CONCLUSION: Our results suggest that there are modifiable targets to maintain gait speed that are amenable to potential treatment.

PMID: 33429086 [PubMed - as supplied by publisher]

Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.

Proc Natl Acad Sci U S A. 2021 Jan 26;118(4):

Authors: Giovinazzo D, Bursac B, Sbodio JI, Nalluru S, Vignane T, Snowman AM, Albacarys LM, Sedlak TW, Torregrossa R, Whiteman M, Filipovic MR, Snyder SH, Paul BD

Abstract
Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

PMID: 33431651 [PubMed - in process]

Anti-senescent drug screening by deep learning-based morphology senescence scoring.

Nat Commun. 2021 01 11;12(1):257

Authors: Kusumoto D, Seki T, Sawada H, Kunitomi A, Katsuki T, Kimura M, Ito S, Komuro J, Hashimoto H, Fukuda K, Yuasa S

Abstract
Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.

PMID: 33431893 [PubMed - indexed for MEDLINE]

The distribution of cellular turnover in the human body.

Nat Med. 2021 01;27(1):45-48

Authors: Sender R, Milo R

Abstract
We integrated ubiquity, mass and lifespan of all major cell types to achieve a comprehensive quantitative description of cellular turnover. We found a total cellular mass turnover of 80 ± 20 grams per day, dominated by blood cells and gut epithelial cells. In terms of cell numbers, close to 90% of the (0.33 ± 0.02) × 1012 cells per day turnover was blood cells.

PMID: 33432173 [PubMed - indexed for MEDLINE]

Spatial correlations constrain cellular lifespan and pattern formation in corneal epithelium homeostasis.

Elife. 2021 Jan 12;10:

Authors: Strinkovsky L, Havkin E, Shalom-Feuerstein R, Savir Y

Abstract
Homeostasis in adult tissues relies on the replication dynamics of stem cells, their progenitors and the spatial balance between them. This spatial and kinetic coordination is crucial to the successful maintenance of tissue size and its replenishment with new cells. However, our understanding of the role of cellular replicative lifespan and spatial correlation between cells in shaping tissue integrity is still lacking. We developed a mathematical model for the stochastic spatial dynamics that underlie the rejuvenation of corneal epithelium. Our model takes into account different spatial correlations between cell replication and cell removal. We derive the tradeoffs between replicative lifespan, spatial correlation length, and tissue rejuvenation dynamics. We determine the conditions that allow homeostasis and are consistent with biological timescales, pattern formation, and mutants phenotypes. Our results can be extended to any cellular system in which spatial homeostasis is maintained through cell replication.

PMID: 33433326 [PubMed - in process]

Pentapeptide repeat protein QnrB1 requires ATP hydrolysis to rejuvenate poisoned gyrase complexes.

Nucleic Acids Res. 2021 Jan 12;:

Authors: Mazurek Ł, Ghilarov D, Michalczyk E, Pakosz Z, Metelev M, Czyszczoń W, Wawro K, Behroz I, Dubiley S, Süssmuth RD, Heddle JG

Abstract
DNA gyrase, a type II topoisomerase found predominantly in bacteria, is the target for a variety of 'poisons', namely natural product toxins (e.g. albicidin, microcin B17) and clinically important synthetic molecules (e.g. fluoroquinolones). Resistance to both groups can be mediated by pentapeptide repeat proteins (PRPs). Despite long-term studies, the mechanism of action of these protective PRPs is not known. We show that a PRP, QnrB1 provides specific protection against fluoroquinolones, which strictly requires ATP hydrolysis by gyrase. QnrB1 binds to the GyrB protein and stimulates ATPase activity of the isolated N-terminal ATPase domain of GyrB (GyrB43). We probed the QnrB1 binding site using site-specific incorporation of a photoreactive amino acid and mapped the crosslinks to the GyrB43 protein. We propose a model in which QnrB1 binding allosterically promotes dissociation of the fluoroquinolone molecule from the cleavage complex.

PMID: 33434265 [PubMed - as supplied by publisher]

Elastic fibers during aging and disease.

Ageing Res Rev. 2021 Jan 09;66:101255

Authors: Heinz A

Abstract
Elastic fibers are essential constituents of the extracellular matrix of higher vertebrates and endow several tissues and organs including lungs, skin and blood vessels with elasticity and resilience. During the human lifespan, elastic fibers are exposed to a variety of enzymatic, chemical and biophysical influences, and accumulate damage due to their low turnover. Aging of elastin and elastic fibers involves enzymatic degradation, oxidative damage, glycation, calcification, aspartic acid racemization, binding of lipids and lipid peroxidation products, carbamylation and mechanical fatigue. These processes can trigger an impairment or loss of elastic fiber function and are associated with severe pathologies. There are different inherited or acquired pathological conditions, which influence the structure and function of elastic fibers and microfibrils predominantly in the cardiorespiratory system and skin. Inherited elastic-fiber pathologies have a direct or indirect impact on elastic-fiber formation due to mutations in the fibrillin genes (fibrillinopathies), in the elastin gene (elastinopathies) or in genes encoding proteins that are associated with microfibrils or elastic fibers. Acquired elastic-fiber pathologies appear age-related or as a result of multiple factors impairing tissue homeostasis. This review gives an overview on the fate of elastic fibers over the human lifespan in health and disease.

PMID: 33434682 [PubMed - as supplied by publisher]

Effects of tart cherry and its metabolites on aging and inflammatory conditions: Efficacy and possible mechanisms.

Ageing Res Rev. 2021 Jan 09;66:101254

Authors: Mansoori S, Dini A, Chai SC

Abstract
Inflammation is an underlying cause of or a contributing factor to a number of chronic conditions, including hypertension, insulin resistance, arthritis, and cognitive disorders. A chronic inflammatory state is also associated with aging. Tart cherry (TC) has been extensively studied for its ability to prevent or treat inflammatory diseases and their associated risk factors. TC contains active compounds, including polyphenols that may contribute to its antioxidant and anti-inflammatory effects. Inflammatory signaling pathways regulate the recruitment of inflammatory cells important for the pathogenesis of disease. Whole TC, individual compounds, and their metabolites may be viable treatment options because they can target molecules involved in inflammatory pathways. In this review, the effectiveness of TC in reducing inflammatory markers associated with chronic diseases and the effects of the active compounds in TC and their metabolites on inflammatory pathways are discussed. The main polyphenols present in TC include cyanidins, kaempferol, quercetin, melatonin, neochlorogenic acid, chlorogenic acid, and 3-coumaroylquinic acid. Evidence supports an association between TC intake and reduced risk for inflammatory disease, which may be due to the effects of active compounds in TC on inflammatory pathways, such as NF-κB and mitogen-activated protein kinase.

PMID: 33434683 [PubMed - as supplied by publisher]

Monoamine oxidases in age-associated diseases: New perspectives for old enzymes.

Ageing Res Rev. 2021 Jan 09;66:101256

Authors: Santin Y, Resta J, Parini A, Mialet-Perez J

Abstract
Population aging is one of the most significant social changes of the twenty-first century. This increase in longevity is associated with a higher prevalence of chronic diseases, further rising healthcare costs. At the molecular level, cellular senescence has been identified as a major process in age-associated diseases, as accumulation of senescent cells with aging leads to progressive organ dysfunction. Of particular importance, mitochondrial oxidative stress and consequent organelle alterations have been pointed out as key players in the aging process, by both inducing and maintaining cellular senescence. Monoamine oxidases (MAOs), a class of enzymes that catalyze the degradation of catecholamines and biogenic amines, have been increasingly recognized as major producers of mitochondrial ROS. Although well-known in the brain, evidence showing that MAOs are also expressed in a variety of peripheral organs stimulated a growing interest in the extra-cerebral roles of these enzymes. Besides, the fact that MAO-A and/or MAO-B are frequently upregulated in aged or dysfunctional organs has uncovered new perspectives on their roles in pathological aging. In this review, we will give an overview of the major results on the regulation and function of MAOs in aging and age-related diseases, paying a special attention to the mechanisms linked to the increased degradation of MAO substrates or related to MAO-dependent ROS formation.

PMID: 33434685 [PubMed - as supplied by publisher]

Widespread reworking of Hadean-to-Eoarchean continents during Earth's thermal peak.

Nat Commun. 2021 Jan 12;12(1):331

Authors: Kirkland CL, Hartnady MIH, Barham M, Olierook HKH, Steenfelt A, Hollis JA

Abstract
The nature and evolution of Earth's crust during the Hadean and Eoarchean is largely unknown owing to a paucity of material preserved from this period. However, clues may be found in the chemical composition of refractory minerals that initially grew in primordial material but were subsequently incorporated into younger rocks and sediment during lithospheric reworking. Here we report Hf isotopic data in 3.9 to 1.8 billion year old detrital zircon from modern stream sediment samples from West Greenland, which document successive reworking of felsic Hadean-to-Eoarchean crust during subsequent periods of magmatism. Combined with global zircon Hf data, we show a planetary shift towards, on average, more juvenile Hf values 3.2 to 3.0 billion years ago. This crustal rejuvenation was coincident with peak mantle potential temperatures that imply greater degrees of mantle melting and injection of hot mafic-ultramafic magmas into older Hadean-to-Eoarchean felsic crust at this time. Given the repeated recognition of felsic Hadean-to-Eoarchean diluted signatures, ancient crust appears to have acted as buoyant life-rafts with enhanced preservation-potential that facilitated later rapid crustal growth during the Meso-and-Neoarchean.

PMID: 33436605 [PubMed]

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease.

Nat Commun. 2021 01 12;12(1):330

Authors: Sartori R, Romanello V, Sandri M

Abstract
Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

PMID: 33436614 [PubMed - indexed for MEDLINE]

Molecular mechanisms and physiological functions of mitophagy.

EMBO J. 2021 Feb 01;40(3):e104705

Authors: Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K

Abstract
Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.

PMID: 33438778 [PubMed - in process]

An isocaloric moderately high-fat diet extends lifespan in male rats and Drosophila.

Cell Metab. 2021 Jan 07;:

Authors: Shi D, Han T, Chu X, Lu H, Yang X, Zi T, Zhao Y, Wang X, Liu Z, Ruan J, Liu X, Ning H, Wang M, Tian Z, Wei W, Sun Y, Li Y, Guo R, Wang Y, Ling F, Guan Y, Shen D, Niu Y, Li Y, Sun C

Abstract
The health effect of dietary fat has been one of the most vexing issues in the field of nutrition. Few animal studies have examined the impact of high-fat diets on lifespan by controlling energy intake. In this study, we found that compared to a normal diet, an isocaloric moderately high-fat diet (IHF) significantly prolonged lifespan by decreasing the profiles of free fatty acids (FFAs) in serum and multiple tissues via downregulating FFA anabolism and upregulating catabolism pathways in rats and flies. Proteomics analysis in rats identified PPRC1 as a key protein that was significantly upregulated by nearly 2-fold by IHF, and among the FFAs, only palmitic acid (PA) was robustly and negatively associated with the expression of PPRC1. Using PPRC1 transgenic RNAi/overexpression flies and in vitro experiments, we demonstrated that IHF significantly reduced PA, which could upregulate PPRC1 through PPARG, resulting in improvements in oxidative stress and inflammation and prolonging the lifespan.

PMID: 33440166 [PubMed - as supplied by publisher]