Vadim N. Gladyshev

Vadim N. Gladyshev is a professor of medicine at Brigham and Women's Hospital, Harvard Medical School, who specializes in antioxidant biology. He is known for his characterization of the human selenoproteome. He is also known for his work on the effects of aging in humans. He has conducted studies on whether organisms can acquire cellular damage from their food; the role selenium plays as a micro-nutrient with significant health benefits; In 2013 he won the NIH Pioneer Award.

In 2021, he was elected member of the U. S. National Academy of Sciences.

Research
Vadim Gladyshev's primary research focus on understanding the mechanisms behind aging, lifespan control, and rejuvenation. His work spans various dimensions of biology, including selenium biochemistry and redox biology, but is most notably recognized for his contributions to the study of longevity and the aging process.

Gladyshev's laboratory has made significant strides in uncovering the molecular bases for natural variations in lifespan across different species. By studying long-lived organisms, such as naked mole-rats and microbats, and analyzing large datasets across mammals or yeast isolates, his team aims to identify "longevity signatures." These signatures are molecular patterns, derived from transcriptomic, metabolomic, or proteomic analyses, that highlight cellular pathways associated with extended lifespan.

In his pursuit of understanding lifespan extension, Gladyshev has examined interventions known to prolong life in mice, discovering shared metabolic remodeling processes across various strategies. His research has revealed multiple pathways to lifespan extension, whether through species comparison, interventions, or cellular longevity, posing the challenge of integrating these discoveries to maximize lifespan extension.

Another innovative avenue of Gladyshev's work is the unbiased identification of lifespan-extending interventions. Using longevity signatures, his team screens for new dietary, pharmacological, and genetic strategies that promise to increase lifespan, incorporating omics approaches and physiological assays to assess their efficacy. This approach has also been applied to cancer studies, particularly focusing on B-cell lymphoma.

Gladyshev's interest in age reversal and rejuvenation has led to groundbreaking discoveries. He actively employs Yamanaka-type approaches for reprogramming somatic cells to induced pluripotent stem cells and investigates the biological age reduction during early embryogenesis. His research aims to apply these rejuvenation strategies to extend lifespan and healthspan significantly.

What is "Aging"?
In his quest to further understand aging, Vadim Gladyshev conducted a survey among experts in the field, revealing a significant lack of consensus on the foundational aspects of aging. Questions such as the essence of aging, its causes, the onset, and the nature of rejuvenation garnered diverse responses, underscoring the complexity and multifaceted nature of aging research. This divergence in opinion not only highlights the challenge in defining aging but also the variability in approaches to studying and understanding this inevitable biological process.

Gladyshev's survey sheds light on the attempt by many in the field to describe aging through associations or features rather than a singular definition. This includes views of aging as an accumulation of damage, functional decline, and increased mortality rate, among others. However, this approach often results in definitions that lack explanatory power or are overly broad, failing to capture the essence of aging.

The survey also underscored the disconnection between contemporary thinking about aging and the actual focus of research in the field. Despite the importance of these foundational questions, there is little effort directed towards addressing them directly, partly due to the difficulty in designing experiments or treatments that can conclusively answer these questions. Additionally, the terminology used to describe aging is often ill-defined, further complicating the dialogue and research in this area.

Gladyshev's work, both through his ground zero hypothesis and his exploration of the fundamental nature of aging, invites a reevaluation of how aging is studied and understood. By challenging the field to confront these essential questions head-on, he paves the way for more coherent and targeted research efforts, potentially unlocking new pathways for intervention and a deeper understanding of the aging process.

Ground Zero Hypothesis
Vadim has introduced a pioneering model known as 'ground zero'. This concept centers around the mid-embryonic state of gastrulation, a pivotal period characterized by a potentially lowest biological age, signifying the commencement of organismal life and the aging process. Gladyshev suggests that this phase not only marks the beginning of aging but also represents a unique opportunity for rejuvenation. The zygote to ground zero transition is thought to be a rejuvenating phase, where the biological age is decreased, telomeres are elongated, and molecular damage is effectively cleared.

This ground zero of aging aligns with the phylotypic period within the evolutionary hourglass model, proposing a fundamental state in development across species that could be crucial for understanding aging and rejuvenation at a molecular level. By extending this rejuvenation phase or manipulating the genome during early embryogenesis, Gladyshev posits that it might be possible to achieve even lower biological ages than naturally occur, offering a groundbreaking approach to aging research.

Aging Clocks and Biomarkers
Following in the footsteps of pioneers like Steve Horvath, Gladyshev has developed the first mouse epigenetic aging clocks. These tools can measure the effects of longevity interventions and the transition from fibroblasts to iPSCs. His work extends to developing scalable epigenetic age profiling methods at single-cell resolution and cost-effective biological age profiling in bulk samples, contributing valuable tools for biological age assessment and age reversal research.

Deleteriome and Selenium Research
Gladyshev introduced the concept of the "deleteriome," proposing it as a fundamental characteristic defining aging by representing molecular damage and other metabolic byproducts. His theoretical and experimental work aims to discern the true nature of aging, which is crucial in the era of age reversal research.

In addition to his aging research, Gladyshev is renowned for his discovery of the full set of 25 human selenoprotein genes, exploring the biological roles of selenium in organisms. His work on selenium metabolism and redox regulation offers insights into essential cellular processes and their implications for aging and cancer.

Redox Biology
Gladyshev's lab also delves into redox biology, seeking to understand how redox processes are regulated within cells and their impact on aging and cancer. By developing bioinformatics tools and conducting extensive genome sequencing and functional genomics studies, his research endeavors to uncover the mechanisms of redox control and its participants.