scholarly journals Klotho: An Elephant in Aging Research

2019 ◽  
Vol 74 (7) ◽  
pp. 1031-1042 ◽  
Author(s):  
Amin Cheikhi ◽  
Aaron Barchowsky ◽  
Amrita Sahu ◽  
Sunita N Shinde ◽  
Abish Pius ◽  
...  
Keyword(s):  
Life Span ◽  
Accelerated Aging ◽  
Model Organisms ◽  
Aging Research ◽  
Promising Tool ◽  
Age Related ◽  
Organ Systems ◽  
Single Protein ◽  
20Th Anniversary ◽  
Biology Of Aging

Abstract The year 2017 marked the 20th anniversary of the first publication describing Klotho. This single protein was and is remarkable in that its absence in mice conferred an accelerated aging, or progeroid, phenotype with a dramatically shortened life span. On the other hand, genetic overexpression extended both health span and life span by an impressive 30%. Not only has Klotho deficiency been linked to a number of debilitating age-related illnesses but many subsequent reports have lent credence to the idea that Klotho can compress the period of morbidity and extend the life span of both model organisms and humans. This suggests that Klotho functions as an integrator of organ systems, making it both a promising tool for advancing our understanding of the biology of aging and an intriguing target for interventional studies. In this review, we highlight advances in our understanding of Klotho as well as key challenges that have somewhat limited our view, and thus translational potential, of this potent protein.

scholarly journals Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

2009 ◽  
Vol 9 ◽  
pp. 1449-1462 ◽  
Author(s):  
Baomin Li ◽  
Sonali Jog ◽  
Jose Candelario ◽  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Natural Aging ◽  
Aging Research ◽  
Cellular Processes ◽  
Functional Connections ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

scholarly journals Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging

2020 ◽  
Author(s):  
Line Jee Hartmann Rasmussen ◽  
Avshalom Caspi ◽  
Antony Ambler ◽  
Andrea Danese ◽  
Maxwell Elliott ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Functional Decline ◽  
Accelerated Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Blood Levels ◽  
Urokinase Plasminogen Activator Receptor ◽  
Reactive Protein ◽  
Age Related ◽  
Organ Systems

Abstract Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

scholarly journals Finding Ponce de Leon’s Pill: Challenges in Screening for Anti-Aging Molecules

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 406 ◽  
Author(s):  
Surinder Kumar ◽  
David B. Lombard
Keyword(s):  
Model Organisms ◽  
Cancer Type ◽  
Pharmacological Interventions ◽  
Aging Research ◽  
Genetic Manipulations ◽  
Age Related ◽  
Probability Of Death ◽  
Invertebrate Models ◽  
Progressive Accumulation

Aging is characterized by the progressive accumulation of degenerative changes, culminating in impaired function and increased probability of death. It is the major risk factor for many human pathologies – including cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases – and consequently exerts an enormous social and economic toll. The major goal of aging research is to develop interventions that can delay the onset of multiple age-related diseases and prolong healthy lifespan (healthspan). The observation that enhanced longevity and health can be achieved in model organisms by dietary restriction or simple genetic manipulations has prompted the hunt for chemical compounds that can increase lifespan. Most of the pathways that modulate the rate of aging in mammals have homologs in yeast, flies, and worms, suggesting that initial screening to identify such pharmacological interventions may be possible using invertebrate models. In recent years, several compounds have been identified that can extend lifespan in invertebrates, and even in rodents. Here, we summarize the strategies employed, and the progress made, in identifying compounds capable of extending lifespan in organisms ranging from invertebrates to mice and discuss the formidable challenges in translating this work to human therapies.

scholarly journals Opportunities for organoids as new models of aging

2017 ◽  
Vol 217 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Jennifer L. Hu ◽  
Michael E. Todhunter ◽  
Mark A. LaBarge ◽  
Zev J. Gartner
Keyword(s):  
Cell Culture ◽  
Animal Studies ◽  
Model Organisms ◽  
Human Tissues ◽  
Human Cell Culture ◽  
Aging Research ◽  
New Models ◽  
Culture Models ◽  
Biology Of Aging ◽  
Cell Culture Models

The biology of aging is challenging to study, particularly in humans. As a result, model organisms are used to approximate the physiological context of aging in humans. However, the best model organisms remain expensive and time-consuming to use. More importantly, they may not reflect directly on the process of aging in people. Human cell culture provides an alternative, but many functional signs of aging occur at the level of tissues rather than cells and are therefore not readily apparent in traditional cell culture models. Organoids have the potential to effectively balance between the strengths and weaknesses of traditional models of aging. They have sufficient complexity to capture relevant signs of aging at the molecular, cellular, and tissue levels, while presenting an experimentally tractable alternative to animal studies. Organoid systems have been developed to model many human tissues and diseases. Here we provide a perspective on the potential for organoids to serve as models for aging and describe how current organoid techniques could be applied to aging research.

scholarly journals Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span

Science ◽  
2021 ◽  
Vol 373 (6554) ◽  
pp. eabc8479
Author(s):  
M. Grunewald ◽  
S. Kumar ◽  
H. Sharife ◽  
E. Volinsky ◽  
A. Gileles-Hillel ◽  
...  
Keyword(s):  
Life Span ◽  
Healthy Aging ◽  
Vascular Diseases ◽  
Tumor Burden ◽  
Multiple Organ ◽  
Vegf Signaling ◽  
Established Risk Factor ◽  
Age Related ◽  
Organ Systems ◽  
And Function

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

scholarly journals A novel approach to assess the dynamics of extra-chromosomal circular ribosomal DNA in human cells

2014 ◽  
Author(s):  
Joerg R Leheste ◽  
Emily Forbes ◽  
Kristin DiGregorio ◽  
Victoria Katz ◽  
Alyssa Miceli ◽  
...  
Keyword(s):  
Life Span ◽  
Signaling Pathways ◽  
Ribosomal Dna ◽  
Experimental Manipulation ◽  
Human Cells ◽  
Model Organisms ◽  
Age Related ◽  
Novel Approach ◽  
Extend Life Span ◽  
Nutrient Signaling

Several nutrient-signaling pathways that extend life span have been described in model organisms. Thus, parallel and redundant signaling pathways that are similar across species might be subject to experimental manipulation. Here, we develop a PCR-based technique for testing the hypothesis that mitotic accumulation of extra-chromosomal ribosomal DNA circles might also determine life span in human cells. Using resveratrol, a phytochemical that counters age-related signs, we find treatment-dependent subcellular accumulations of extra-chromosomal 5S ribosomal DNA in human cell lines. These data suggest an association between DNA circles and intrinsic aging and demonstrate the utility of a PCR-based technique for studying the accumulation of dysfunctional molecules that promote senescence.

scholarly journals CDKN2A Gene Expression as a Potential Aging Biomarker in Dogs

2021 ◽  
Vol 8 ◽  
Author(s):  
Sára Sándor ◽  
Kitti Tátrai ◽  
Kálmán Czeibert ◽  
Balázs Egyed ◽  
Enikő Kubinyi
Keyword(s):  
Gene Expression ◽  
Kinase Inhibitor ◽  
Brain Aging ◽  
Model Organisms ◽  
Aging Research ◽  
Temporal Muscle ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Age Related ◽  
The Brain

Describing evolutionary conserved physiological or molecular patterns, which can reliably mark the age of both model organisms and humans or predict the onset of age-related pathologies has become a priority in aging research. The age-related gene-expression changes of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene have been well-documented in humans and rodents. However, data is lacking from other relevant species, including dogs. Therefore, we quantified the CDKN2A mRNA abundance in dogs of different ages, in four tissue types: the frontal cortex of the brain, temporal muscle, skin, and blood. We found a significant, positive correlation between CDKN2A relative expression values and age in the brain, muscle, and blood; however, no correlation was detected in the skin. The strongest correlation was detected in the brain tissue (CDKN2A/GAPDH: r = 0.757, p < 0.001), similarly to human findings, while the muscle and blood showed weaker, but significant correlation. Our results suggest that CDKN2A might be a potential blood-borne biomarker of aging in dogs, although the validation and optimization will require further, more focused research. Our current results also clearly demonstrate that the role of CDKN2A in aging is conserved in dogs, regarding both tissue specificity and a pivotal role of CDKN2A in brain aging.

scholarly journals Quantification of biological aging in young adults

2015 ◽  
Vol 112 (30) ◽  
pp. E4104-E4110 ◽  
Author(s):  
Daniel W. Belsky ◽  
Avshalom Caspi ◽  
Renate Houts ◽  
Harvey J. Cohen ◽  
David L. Corcoran ◽  
...  
Keyword(s):  
Young Adults ◽  
Brain Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Research Translation ◽  
Human Aging ◽  
Aging Research ◽  
Cross Sectional ◽  
Age Related ◽  
Organ Systems

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

scholarly journals The Translational Geroscience Network: Supporting a New Paradigm to Alleviate Age-Related Chronic Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 831-831
Author(s):  
Jamie Justice ◽  
Stephen Kritchevsky ◽  
George Kuchel ◽  
James Kirkland
Keyword(s):  
Biological Aging ◽  
Small Scale ◽  
New Paradigm ◽  
Aging Research ◽  
Age Related ◽  
Treatment Focus ◽  
Working Together ◽  
Basic Biology ◽  
Biology Of Aging ◽  
Traditional Approaches

Abstract Aging is the leading risk factor for many chronic diseases. Through traditional approaches to drug development and treatment focus on treating one disease at a time, the geroscience hypothesis posits that by targeting fundamental aging processes one could alleviate multiple age-related diseases. Now several geroscience-guided interventions are at the point of entering human clinical trials. To accelerate testing of this important hypothesis, an interdisciplinary Translational Geroscience Network (TGN; R33 AG061456) has recently been established. The TGN is a new national resource of aging research centers committed to working together toward complementary, small-scale, proof-of-concept “use case” clinical studies. One such pilot will be highlighted: a translational trial of senolytics, or drugs targeting the biological aging process cellular senescence in patients with idiopathic pulmonary fibrosis. The promise of geroscience provides another reason “why age matters”: by studying the basic biology of aging, we may open novel therapeutic opportunities for challenging age-related diseases.

scholarly journals Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3577
Author(s):  
Maria S. Manola ◽  
Sentiljana Gumeni ◽  
Ioannis P. Trougakos
Keyword(s):  
Accelerated Aging ◽  
Model Organisms ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Age Related ◽  
Wide Range ◽  
Transgenic Lines ◽  
Ubiquitin Proteasome ◽  
Increased Sensitivity ◽  
Proteasome Pathway

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.

Sign in / Sign up

Export Citation Format

Share Document