Research Abstract
Research in our lab revolves primarily around aging, lifespan control and rejuvenation.
We also have had longstanding interests in selenium and redox biology.
Understanding mechanisms of lifespan control through longevity signatures
Mice live 3 years, dogs 15 years and humans 100 years, even if they are exposed to the same environment. It is easy to change species lifespan over evolutionary times, e.g., mammals differ more than 100-fold in lifespan. We uncover molecular bases for natural changes in longevity by focusing on exceptionally long-lived organisms, such as naked mole-rats and microbats, and performing analyses across large panels of related species (e.g., mammals) or isolates of the same species (e.g., yeast). We sequence and analyze the genomes of these organisms, develop iPSCs and carry out large-scale omics analyses across their various tissues and single cells. Subsequent application of computational approaches generates longevity signatures, which are molecular patterns (e.g., based on the transcriptome, metabolome or proteome), which point to cellular pathways and systems associated with extended lifespan. In other words, these longevity signatures report the potential to live long.
Additionally, we develop longevity signatures across interventions known to extend lifespan. Here, the mouse is our main model organism. There are more than two dozen well-established interventions that extend the lifespan of mice. We found that many of these interventions, such as calorie restriction, growth hormone receptor deficiency or overexpression of certain factors similarly remodel metabolism, thereby extending lifespan via shared mechanisms. This type of longevity is also associated with the effect of feminization. On the other hand, there are also many other interventions that remodel metabolism differently, yet still extend lifespan. A third type of longevity signatures that we examine is the signature across cell types. For example, neurons are formed during embryonic development and live for the entire life of the organism, whereas some cells in the blood are short-lived. The resulting omics profiles are integrated across all three signature types to better understand the nature of cell, tissue and organismal remodeling that leads to lifespan extension.
Our studies revealed that there are many ways to extend lifespan, whether we consider longevity across species, interventions or cell types. A challenge for future studies is to identify and understand molecular underpinnings of the most robust longevity signatures, and to develop approaches that combine them to achieve the most significant lifespan extension.
Unbiased identification of interventions that extend lifespan
The three types of longevity signatures described above can be used directly in screens for new dietary, pharmacological and genetic interventions that extend lifespan. We carry out such screens in cell culture and animal models, assisted by omics approaches and physiological assays, and have already identified many new candidate longevity interventions. We assess and evaluate them with lifespan experiments, frailty analyses, transcriptomic profiling, changes in biological age (as measured by clocks), as well as other assays. We also apply machine learning approaches to predict the effects of candidate interventions based on their impact on molecular patterns in vitro and in vivo. This research results in the unbiased identification of new interventions that extend lifespan. This project also involves studies on cancer, as this is the main cause of death in mice. We have focused in the past on liver cancer, and our major current focus is B-cell lymphoma. We have made significant progress by focusing initially on pharmacological interventions, but are seeking to expand to genetic manipulations and dietary or environmental factors.
Age reversal and rejuvenation
A recent striking realization in the aging field is that aging not only can be slowed down, but organisms can be partially rejuvenated, i.e., their biological age can actually be reduced. This is already clear from experiments on reprogramming of somatic cells to induced pluripotent stem cells by Yamanaka-type approaches, which we actively use in the lab. In addition, we discovered that early embryogenesis, the period around gastrulation, is associated with robust biological age reduction. This is needed to achieve the same low biological age to begin organismal life in each generation. We also found that the age can be reversed by other approaches, such as long-term heterochronic parabiosis. Understanding mechanisms of age reduction may allow, in the future, to apply these strategies to various cells and systems, thereby radically extending lifespan and healthspan. We seek to develop rejuvenation signatures, by analogy to longevity signatures, and use them to screen for interventions that decrease biological age.
Aging clocks and other biomarkers of biological age
Following pioneering studies on human epigenetic clocks by Steve Horvath, we developed the first mouse epigenetic aging clocks, which could report the effects of longevity interventions and the conversion of fibroblasts to iPSCs. We have published papers on blood, multi-tissue and rDNA-based epigenetic clocks. Very recently, we developed the first single-cell clock—scAge—a framework for accurate and scalable epigenetic age profiling at single-cell resolution. We additionally developed approaches for cost-effective profiling of biological age in bulk samples, which supports up to 100-1000-fold reduction in per-sample sequencing costs. Excitingly, these approaches can be used in high-throughput screens and analyses of large tissue collections and biobanks. Finally, we develop next generation single-cell multi-omic approaches for the analysis of biological age. These clocks and biomarkers provide tools for the assessment of biological age and age reversal across a variety of settings.
Deleteriome and the nature of the aging process
Studying aging without understanding its true nature is akin to medieval alchemists attempting to make gold. Yet, there is no consensus in the field on some of the most important critical issues, including the nature of aging, its beginning, and what should be targeted if we seek to target “aging”. Various scientists believe that aging is analogous to 1) increased age-related mortality, 2) loss of function, 3) decreased fitness, 4) “a period after development”, 5) increased biological age, 6) age-related changes, etc… While all these features admittedly characterize aging later in life, there must be one, most fundamental feature that defines others. We’ve developed a theoretical framework on aging, proposing the concept of the deleteriome, which represents molecular damage and other negative consequences of being metabolically alive. In this model, the deleteriome is the primary feature, which leads (or sometimes does not, depending on the particular organism, life period, etc.) to increased mortality and loss of function. We recently revealed that aging begins during early embryogenesis (around gastrulation) and runs in parallel with development. We published several studies developing conceptual frameworks of aging and reported experimental studies that support this model. These studies become even more important in this era of age reversal, as it is important to understand what should actually be reversed. Many age-related changes are neutral or protective, and their reversal does not mean the biological age is reduced.
Selenoproteins and the micronutrient element selenium
Our lab is well known for the discovery of the full set of 25 selenoprotein genes in humans, and we previously characterized selenoproteomes (sets of selenoproteins) in all major model organisms as well as in organisms across the tree of life. Selenium is present in proteins in the form of the 21st amino acid, selenocysteine, encoded by the UGA codon. Selenocysteine can be viewed as a redox “supercysteine” because it is used as the catalytic residue in oxidoreductases. By identifying and characterizing the sets of selenoproteins in organisms, we infer the biological role of the trace element selenium. For example, in mammals, major redox systems are dependent on selenium, which is an essential component of various redox enzymes in thioredoxin, glutathione and methionine sulfoxide reduction pathways. We characterize functions, regulation and specific targets of selenoproteins and other oxidoreductases to gain a system-wide view on selenium metabolism and its redox regulation of cellular processes. In particular, we apply genetic tools, ionomic approaches, and ribosome profiling. Most of these studies involve mice. We are also interested in selenocysteine insertion machinery and gene evolution.
Redox biology
We also work to understand mechanisms of redox regulation of cellular processes. Little is known about the specific targets of reactive oxygen species and how oxidant and antioxidant signals are transmitted in the cell. To understand mechanisms of redox control and its role in aging and cancer, we need to know identities and functions of participants in the redox process. Thus, we are developing bioinformatics approaches and carrying out genome sequencing, proteomics and functional genomics studies, which are followed with in vitro and in vivo tests of identified targets. We are particularly interested in the redox control that involves oxidation of cysteine and methionine residues in proteins. For example, we have developed methods for the identification of catalytic redox active cysteines and reported that proteins can be regulated by reversible stereospecific site-specific methionine oxidation, a novel regulatory posttranslational modification.
