Mapping mitochondrial aging.

Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Evidence that C/EBP-β LAP Increases Fat Metabolism and Protects Against Diet-Induced Obesity in Response to mTOR Inhibition.

Aging and obesity are common risk factors for numerous chronic pathologies, and the compounding effects of old age and increased adiposity pose a serious threat to public health. Starting from the assumption that aging and obesity may have shared underpinnings, we investigated the antiobesogenic potential of a successful longevity intervention, the mTORC1 inhibitor rapamycin. We find that rapamycin prevents diet-induced obesity in mice and increases the activity of C/EBP-β LAP, a transcription factor that regulates the metabolic shift to lipid catabolism observed in response to calorie restriction.

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment.

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs elamipretide (SS-31) and nicotinamide mononucleotide (NMN) to reverse aging-associated changes in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are altered with age, while also inducing additional changes. Age-related increases in protein acetylation were predominantly in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling.

Antiaging diets: Separating fact from fiction.

Caloric restriction has been known for nearly a century to extend life span and delay age-associated pathology in laboratory animals. More recently, alternative “antiaging” diet modalities have been described that provide new mechanistic insights and potential clinical applications. These include intermittent fasting, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction, and dietary restriction of specific amino acids.

University of Washington Nathan Shock Center: innovation to advance aging research.

The University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging provides leadership and resources to support the geroscience community locally, nationally, and internationally. Services are provided through our Resource Cores and funds are available annually to support pilot projects by external investigators. Aging-related studies involving proteomics, metabolomics, invertebrate model organisms, and bioinformatics/artificial intelligence are supported by our Cores.

The AGE Presents Introduction to Geroscience video lecture series.

The AGE Presents Introduction to Geroscience video lecture series is a collection of high-quality didactic video lectures and associated teaching materials focused on foundational topics in aging biology. The videos are made freely available on YouTube and are targeted toward an audience familiar with concepts learned in the first year of a college undergraduate biology/biomedical major. Members of the American Aging Association also receive the original lecture slides and lecture notes, with additional course materials to be developed in the future.

The NDUFS4 Knockout Mouse: A Dual Threat Model of Childhood Mitochondrial Disease and Normative Aging.

Mice missing the Complex I subunit NADH:Ubiquinone Oxidoreductase Fe-S Protein 4 (NDUFS4) of the electron transport chain are a leading model of the severe mitochondrial disease Leigh syndrome. These mice have enabled a better understanding of mitochondrial dysfunction in human disease, as well as in the discovery of interventions that can potentially suppress mitochondrial disease manifestations. In addition, increasing evidence suggests significant overlap between interventions that increase survival in NDUFS4 knockout mice and that extend life span during normative aging.

Proceedings from the annual University of Washington Geroscience Symposium, October 23, 2020.

The University of Washington Nathan Shock Center of Excellence in the Biology of Aging in conjunction with the Healthy Aging and Longevity Research Institute held its annual geroscience symposium virtually on October 23, 2020. The symposium was divided into three sessions: (I) organ aging and growth signaling, (II) neurodegeneration and metabolism, and (III) innovative approaches in geroscience and aging research. Nine speakers affiliated with the University of Washington and three invited guest speakers, predominantly trainee, and junior faculty presented their research.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts.

The effects of two different mitochondrial-targeted drugs, SS-31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS-31 partially reversed an age-related decline in diastolic function while NMN fully reversed an age-related deficiency in systolic function at a higher workload.

The importance of diversity and outreach in geroscience research: Insights from the Annual Biomedical Research Conference for Minority Students.

US academic science lacks racial, ethnic, sex, gender, disability, and socioeconomic diversity. Addressing this problem is essential to drive scientific progress but is confounded by broad misunderstandings regarding diverse groups. Increasing representation in science is particularly relevant in geroscience, where our research to maximize healthy human lifespan must also address existing racial and socioeconomic health disparities.

Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease.

Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration.

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR).

Corrigendum: Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

[This corrects the article on p. 113 in vol. 8, PMID: 28919908.

Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

The inactivation of ribosomal protein S6 kinase 1 (S6K1) recapitulates aspects of caloric restriction and mTORC1 inhibition to achieve prolonged longevity in invertebrate and mouse models. In addition to delaying normative aging, inhibition of mTORC1 extends the shortened lifespan of yeast, fly, and mouse models with severe mitochondrial disease. Here we tested whether disruption of S6K1 can recapitulate the beneficial effects of mTORC1 inhibition in the Ndufs4 knockout (NKO) mouse model of Leigh Syndrome caused by Complex I deficiency.

Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans.

Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice.

Biochemical Genetic Pathways that Modulate Aging in Multiple Species.

The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans.

Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.

Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established.

Rejuvenation: it's in our blood.

It has been known for some time that blood from young mice can positively impact aged animals, while blood from old mice has the opposite effect. Recent studies report that rejuvenating effects of young blood extend to multiple tissues and have identified GDF11 and CCL11 as factors mediating these effects.

Detecting senescence: methods and approaches.

The detection of senescent cells has become an important area of research in the aging field. Due to the complexity of the senescence program and the lack of a unique signature for senescence, the detection of these cells remains problematic. This is especially true for in vivo detection in aged or diseased tissue samples.

The senescence arrest program and the cell cycle.

All living organisms are subject to progressive loss of function and damage to their tissues, a process known as aging. At the cellular level, the accumulation of damage to DNA, proteins, and organelles induces cellular senescence, a stress-response pathway that likely influences the aging process. Although the senescence arrest program was initially described in vitro, accumulating evidence suggests that this damage response program occurs in a variety of pathologic settings.

P62/SQSTM1 at the interface of aging, autophagy, and disease.

Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids.