Warren C. Ladiges, D.V.M, M.S.
Professor
D.V.M., Washington State University, 1971
M.S., Washington State University
Residency training in pathology, UW
Postdoctoral Research Fellowship, FHCRC
Diplomate, ACLA Medicine/Pathology
P: 206-685-3260
E: wladiges@uw.edu
About Dr. Ladiges
Dr. Ladiges’s current research interest is in the discovery and testing of anti-aging therapeutics to treat and prevent aging and disease conditions associated with aging. This concept has the potential to help establish a new approach in treating elderly patients suffering from chronic and often multi-morbid disease conditions by treating aging as a distinct entity with single drugs or drug combinations that target molecular pathways associated with aging.
Dr. Ladiges is Director of the Geropathology Research Network. He has overseen the development of the Geropathology Grading Platform, which is a standard set of guidelines designed to determine the level of severity of lesions in organs from aged mice, and other mammalian species.
Dr. Ladiges is Editor-in-Chief of the journal Pathobiology of Aging and Age-related Diseases. He is Director of the Comparative Mouse Genomics Center and a member of the National
Institute on Aging Review Group, and External Advisory Board, Mutant Mouse Resource and Research Centers.
Research Projects
Geropathology as a measure of biological age. It has recently become apparent that preclinical lifespan experiments are not a completely efficient way to measure anti-aging effects. Additional measures are needed. I founded the Geropathology Research Network funded by an NIH grant as a way to enhance the anatomic and molecular pathology assessment in preclinical studies that can be translated to clinical anti-aging investigations. A Geropathology Grading Platform was developed based on a standard set of guidelines designed to 1) detect the histological presence or absence of low impact lesions; and 2) determine the level of severity of high impact lesions in organs from aged mice. The platform generates a numerical score for each lesion in a specific organ, so that a total lesion score is obtained by adding each lesion score for that organ for one mouse. Total lesion scores are averaged between all mice in a specific cohort to obtain a composite lesion score (CLS) for that organ. The CLS can then be used to compare response to drug treatment over time, determine effect of alterations in gene expression, or investigate impact of environmental challenges in a variety of preclinical aging studies.
Targeting aging to treat dementia and Alzheimer’s disease. The prevalence of neurodegenerative diseases is expected to soar with the number of elderly individuals in both developed and developing countries now rising dramatically. Efforts to find disease-modifying treatments have been largely unsuccessful. These efforts have focused mainly on identifying pathogenic mechanisms specific to each disease process. The relative lack of progress with these approaches and the age-related nature of neurodegenerative disease incidence suggest that modulation of aging per se may be a useful alternative approach for delaying the onset or retarding the progression of neurodegenerative diseases. This concept is supported by an impressive body of knowledge identifying genetic, dietary and pharmacologic interventions that profoundly retard aging and its pathophysiologic effects in a number of invertebrate and murine model systems. Correlative human data suggest that these model system results are relevant to humans. Since cognitive decline and Alzheimer’s disease (AD) are highly linked with increasing age as a risk factor, therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. We are focusing on two targets, neurogenesis and synaptic function, and are currently testing several drugs with respective specificity for these targets using a combination of in vitro cellular models and preclinical experiments in mice.
Physical resilience is a predictor of healthy aging. Physical resilience is the ability of an organism to respond to physical stress, and can be measured with various types of stress tests. The loss of resilience occurs much earlier than the development of frailty. Thus, loss of resilience may result in age-related frailty. When measuring overall resilience, integrative responses involving multiple tissues, organs, and activities are desirable, so as to inform about the overall health status of the animal. Therefore, it is more likely that a battery of stress tests, rather than a single all-encompassing one, will be more informative. An ideal battery of tests should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. We have selected two stressors, sleep deprivation and the chemotherapeutic drug cyclophosphamide, to investigate based on features of duplication as well as translational relevance. Sleep deprivation is a major health concern in developed countries and is associated with increasing age, and is a risk factor for insulin resistance and diabetes and memory loss. About one third of people in developed countries experience some type of chemotherapy in their lifetime, and cyclophosphamide is an excellent representative chemotherapeutic agent to test resilience because it is used extensively in patients for a variety of conditions including cancer and rheumatoid arthritis. It targets several different systems but most specifically the hematopoietic system. The development of resilience as a translational aging signature will provide an additional tool to validate drug responses, generated from preclinical mouse studies, for clinical anti-aging trials.
Genetic variant-based drug discovery targeting conserved pathways of aging. Aging is an important risk factor for most common human diseases, including type 2 diabetes, cardiovascular disease, cancer and neurodegeneration. Rather than exclusively focusing on individual diseases, targeting aging itself could be a fruitful approach for preventing, delaying onset and progression, and possibly even reverting many of the multiple age-related pathological sequelae. Research with model organisms has identified multiple promising genes and pathways that could be manipulated in humans to delay aging and its pathological consequences through pharmacological means. Genetic variation in human populations that can be linked to phenotypes of healthy aging or disease-free longevity provides an opportunity to test this possibility. Due to its extreme complexity, the genetic component of aging is poorly defined. However, experiments of nature such as the natural occurrence of genetic variants in humans that affect longevity and healthspan, offer an ideal starting point for taking interventions that promote healthspan to the next level. The best examples of such “natural mutants” are human centenarians and super-centenarians, many of whom managed to ward off the diseases that normally begin to plague humans at middle age. This project uses a genome-to-drug approach applying sequence analysis of centenarians to the development of drugs able to extend health span in mouse models and ultimately in human clinical studies.
Targeting mitochondria to enhance healthy aging. There are extensive research findings on the central role of mitochondria in cellular aging. Mitochondria produce about 90 per cent of cellular energy, are the major source of intracellular ROS, and are extensively involved in the initiation and execution of apoptosis. As energy output declines with increasing age, the most energetic tissues are preferentially affected resulting in degenerative changes in the CNS, heart, kidney, and skeletal muscle. Age-related decline has been observed in these tissues and is associated with a decline in function in animal models and humans. This increased bioenergetic failure suggests that restoration of mitochondrial bioenergetics may provide an approach to the treatment of chronic diseases of aging and the aging process. The goal is to test the long term effects of mitochondrial specific drugs on age-related physiological function and lifespan. The data generated will provide valuable information on ways to further validate new drugs in preclinical studies and develop strategies for developing clinical anti-aging trials.
Selected publications (7 out of 135)
A geroscience mouse model for Alzheimer’s disease. Darvas M, Keene D, Ladiges W. Pathobiol Aging Age Relat Dis. 2019 May 14
Glycine supplementation extends lifespan of male and female mice. Miller RA, Harrison DE, Astle CM, Bogue MA, Brind J, Fernandez E, Flurkey K, Javors M, Ladiges W, Leeuwenburgh C, Macchiarini F, Nelson J, Ryazanov AG, Snyder J, Stearns TM, Vaughan DE, Strong R. Aging Cell. 2019 Mar 27
Pathobiology of aging and age-related diseases is the official journal of the Geropathology Research Network. Ladiges W. Pathobiol Aging Age Relat Dis. 2019 Mar 18
Measuring biological age in mice using differential mass spectrometry. Bell-Temin H, Yousefzadeh MJ, Bondarenko A, Quarles E, Jones-Laughner J, Robbins PD, Ladiges W, Niedernhofer LJ, Yates NA. Aging (Albany NY). 2019 Feb 11
Modeling Alzheimer’s disease in progeria mice. An age-related concept. Sharma K, Darvas M, Keene CD, Niedernhofer LJ, Ladiges W. Pathobiol Aging Age Relat Dis. 2018 Oct 4
Fisetin is a senotherapeutic that extends health and lifespan. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. EBioMedicine. 2018 May 15
Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat. den Hartigh LJ, Goodspeed L, Wang SA, Kenerson HL, Omer M, O’Brien KD, Ladiges W, Yeung R, Subramanian S. Exp Physiol. 2018 Sep 13