Mitchell B. 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 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.

Caution around the fountain of youth: The scientific and popular literature is full of claims for diets that delay or reverse the aging process (at least in model organisms). But how do these interventions work? Is it the amount of food, the timing of food intake, the proportion of certain macronutrients? In a Review, Lee et al . explore the fact and fiction of dietary prescriptions for a healthier and longer life. They propose that one unifying concept may be convergence on the signaling pathway mediated by the protein kinase mTOR (mechanistic target of rapamycin). Another conclusion is that the efficacy and safety of these diets for humans largely remain to be established. —LBR

The question of why and how some species or individuals within a population live longer than others is among the most important questions in the biology of aging. A particularly useful model to understand the genetic basis and selective forces acting on the plasticity of lifespan are closely related species or ecologically diverse individuals of the same species widely different in lifespan. Here, we analyzed 76 diverse wild isolates of two closely related budding yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus and discovered a diversity of natural intra-species lifespan variation. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. We identified sets of genes and metabolites to regulate aging pathways, many of which have not been previously associated with lifespan regulation. We also identified and characterized long-lived strains with elevated intermediary metabolites and differentially regulated genes for NAD metabolism and the control of epigenetic landscape through chromatin silencing. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness. Overall, our study shows how the environment and natural selection interact to shape diversity of lifespan.

Heterozygous mutations affecting DNA polymerase (Pol) exonuclease domains and homozygous inactivation of mismatch repair (MMR) each 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 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 out-compete 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 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 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 intra-tumoral genetic diversity for future adaptation.

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.

Heterozygous mutations affecting DNA polymerase (Pol) exonuclease domains and homozygous inactivation of mismatch repair (MMR) each 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 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 out-compete 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 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 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 intra-tumoral genetic diversity for future adaptation.