Mitchell Lee

Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type… Show more

Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the “million-molecule challenge”, an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested. Show less

Reduced caloric intake without malnutrition is the oldest known life span–extending intervention. Laboratory studies throughout the 20th century established and confirmed the benefits of caloric restriction (CR) in multiple model systems. CR not only increased life span across evolutionarily distant organisms but also reduced age-associated disease burden and functional decline in these studies. Epidemiological data from human populations is also generally consistent with the idea that lower… Show more

Reduced caloric intake without malnutrition is the oldest known life span–extending intervention. Laboratory studies throughout the 20th century established and confirmed the benefits of caloric restriction (CR) in multiple model systems. CR not only increased life span across evolutionarily distant organisms but also reduced age-associated disease burden and functional decline in these studies. Epidemiological data from human populations is also generally consistent with the idea that lower caloric intake is associated with increased life expectancy. In recent years, numerous diet modalities that are purported to be “antiaging” have sprung from these observations. These diets restrict particular macronutrients (carbohydrates or protein) or feeding intervals and can be divided into those that impose reduced caloric intake versus those that are isocaloric to control diets. Show less

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan (RLS). Phylogenetic analyses pointed… Show more

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan (RLS). Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in RLS across wild yeast isolates, as well as genes, metabolites, and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism, and mitochondrial function in long-lived strains. Overall, our multiomic and lifespan analyses across diverse isolates of the same species shows how gene–environment interactions shape cellular processes involved in phenotypic variation such as lifespan. Show less

As the molecular mechanisms of biological aging become better understood, there is growing interest in identifying interventions that target those mechanisms to promote extended health and longevity. The budding yeast Saccharomyces cerevisiae has served as a premier model organism for identifying genetic and molecular factors that modulate cellular aging and is a powerful system in which to evaluate candidate longevity interventions. Here we screened a collection of natural products and natural… Show more

As the molecular mechanisms of biological aging become better understood, there is growing interest in identifying interventions that target those mechanisms to promote extended health and longevity. The budding yeast Saccharomyces cerevisiae has served as a premier model organism for identifying genetic and molecular factors that modulate cellular aging and is a powerful system in which to evaluate candidate longevity interventions. Here we screened a collection of natural products and natural product mixtures for effects on the growth rate, mTOR-mediated growth inhibition, and replicative lifespan. No mTOR inhibitory activity was detected, but several of the treatments affected growth rate and lifespan. The strongest lifespan shortening effects were observed for green tea extract and berberine. The most robust lifespan extension was detected from an extract of Pterocarpus marsupium and another mixture containing Pterocarpus marsupium extract. These findings illustrate the utility of the yeast system for longevity intervention discovery and identify Pterocarpus marsupium extract as a potentially fruitful longevity intervention for testing in higher eukaryotes. Show less

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… Show more

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. We expect that these lectures will enhance understanding of geroscience among the general public while also providing tools that educators can use in the classroom for high school, undergraduate, and graduate level curricula. Show less

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… Show more

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. Here, we summarize research presented during the symposium. A geroscience special issue, of which this is a part, collects submissions from symposium presenters as well as trainees supported by the Biological Mechanisms of Healthy Aging training program. Show less

Mutations affecting DNA polymerase exonuclease domains or mismatch repair (MMR) generate “mutator” phenotypes capable of driving tumorigenesis. Cancers with both defects exhibit an explosive increase in mutation burden that appears to reach a threshold, consistent with selection acting against further mutation accumulation. In Saccharomyces cerevisiae haploid yeast, simultaneous defects in polymerase proofreading and MMR select for “antimutator” mutants that suppress the mutator phenotype. We… Show more

Mutations affecting DNA polymerase exonuclease domains or mismatch repair (MMR) generate “mutator” phenotypes capable of driving tumorigenesis. Cancers with both defects exhibit an explosive increase in mutation burden that appears to reach a threshold, consistent with selection acting against further mutation accumulation. In Saccharomyces cerevisiae haploid yeast, simultaneous defects in polymerase proofreading and MMR select for “antimutator” mutants that suppress the mutator phenotype. We report here that spontaneous polyploids also escape this “error-induced extinction” and routinely outcompete antimutators in evolved haploid cultures. We performed similar experiments to explore how diploid yeast adapt to the mutator phenotype. We first evolved cells with homozygous mutations affecting polymerase δ proofreading and MMR, which we anticipated would favor tetraploid emergence. While tetraploids arose with a low frequency, in most cultures, a single antimutator clone rose to prominence carrying biallelic mutations affecting the polymerase mutator alleles. Variation in mutation rate between subclones from the same culture suggests that there exists continued selection pressure for additional antimutator alleles. We then evolved diploid yeast modeling MMR-deficient cancers with the most common heterozygous exonuclease domain mutation (POLE-P286R). Although these cells grew robustly, within 120 generations, all subclones carried truncating or nonsynonymous mutations in the POLE-P286R homologous allele (pol2-P301R) that suppressed the mutator phenotype as much as 100-fold. Independent adaptive events in the same culture were common. Our findings suggest that analogous tumor cell populations may adapt to the threat of extinction by polyclonal mutations that neutralize the POLE mutator allele and preserve intratumoral genetic diversity for future adaptation. Show less

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. The American Aging Association (AGE) is committed to… Show more

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. The American Aging Association (AGE) is committed to addressing these issues as part of its larger mission to advance and promote geroscience research. Over the last three years, AGE has sponsored an exhibition booth staffed by trainee leaders to promote our society and research at the Annual Biomedical Research Conference for Minority Students (ABRCMS), an ideal venue to interact with diverse students from across the country. Through our interactions with students, advocates, and representatives from other institutions and societies, we have learned a great deal about how to engage and promote the success of diverse students in the sciences. Here, we share these insights that are helping shape our own outreach efforts. In addition to interacting with ABRCMS attendees, we also learned a great deal about how societies like AGE can partner with other organizations to advance our shared goals and the importance of reaching students early in their academic journey to promote their success. Finally, we consider how to grow our outreach efforts beyond ABRCMS to reach those in disadvantaged areas and support students navigating academic science. Show less

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the… Show more

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the elongated G1 phase of the cell cycle during aging may actually play an important role in allowing aged cells time to repair accumulating DNA damage. Show less

Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences… Show more

Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden. Show less

The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of… Show more

The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding. Show less

Translational geroscience is an interdisciplinary field descended from basic gerontology that seeks to identify, validate, and clinically apply interventions to maximize healthy, disease-free lifespan. In this review, we describe a research pipeline for the identification and validation of lifespan extending interventions. Beginning in invertebrate model systems, interventions are discovered and then characterized using other invertebrate model systems (evolutionary translation), models of… Show more

Translational geroscience is an interdisciplinary field descended from basic gerontology that seeks to identify, validate, and clinically apply interventions to maximize healthy, disease-free lifespan. In this review, we describe a research pipeline for the identification and validation of lifespan extending interventions. Beginning in invertebrate model systems, interventions are discovered and then characterized using other invertebrate model systems (evolutionary translation), models of genetic diversity, and disease models. Vertebrate model systems, particularly mice, can then be utilized to validate interventions in mammalian systems. Collaborative, multi-site efforts, like the Interventions Testing Program (ITP), provide a key resource to assess intervention robustness in genetically diverse mice. Mouse disease models provide a tool to understand the broader utility of longevity interventions. Beyond mouse models, we advocate for studies in companion pets. The Dog Aging Project is an exciting example of translating research in dogs, both to develop a model system and to extend their healthy lifespan as a goal in itself. Finally, we discuss proposed and ongoing intervention studies in humans, unmet needs for validating interventions in humans, and speculate on how differences in survival among human populations may influence intervention efficacy. Show less

The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and… Show more

The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and several strategies are being taken to identify mTORC1 inhibitors with fewer side effects. We describe here a yeast-based growth assay that can be used to screen for novel inhibitors of mTORC1. Show less

BACKGROUND: The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in a laboratory setting often have severe fitness disadvantages in the wild.
AIMS AND METHODS: To obtain an unbiased view on longevity regulation, we analyzed how replicative lifespan is shaped by transcriptional, translational, metabolic, and… Show more

BACKGROUND: The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in a laboratory setting often have severe fitness disadvantages in the wild.
AIMS AND METHODS: To obtain an unbiased view on longevity regulation, we analyzed how replicative lifespan is shaped by transcriptional, translational, metabolic, and morphological factors across 22 wild-type Saccharomyces cerevisiae isolates.
RESULTS: We observed significant differences in lifespan across these strains and found that their longevity is strongly associated with up-regulation of oxidative phosphorylation and respiration and down-regulation of amino- acid and nitrogen compound biosynthesis.
CONCLUSIONS: As calorie restriction and TOR signaling also extend the lifespan by adjusting many of the identified pathways, the data suggest that the natural plasticity of yeast lifespan is shaped by the processes that not only do not impose cost on fitness, but also are amenable to dietary intervention. Show less