Vadim N. Gladyshev

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Vadim N. Gladyshev
Born
Vadim N. Gladyshev
Alma mater
Scientific career
Fields Aging
Institutions
Website gladyshevlab.bwh.harvard.edu

Vadim N. Gladyshev is a professor of medicine at Brigham and Women's Hospital, [1] Harvard Medical School, who specializes in antioxidant biology. He is known for his characterization of the human selenoproteome. [2] He is also known for his work on the effects of aging in humans. [3] [4] [5] He has conducted studies on whether organisms can acquire cellular damage from their food; [6] the role selenium plays as a micro-nutrient with significant health benefits; [7] In 2013 he won the NIH Pioneer Award. [8]

Contents

In 2021, he was elected member of the U. S. National Academy of Sciences. [9]

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. [10] 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.

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. The word senescence can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

<span class="mw-page-title-main">Glutathione peroxidase</span> Enzyme family protecting the organism from oxidative damages

Glutathione peroxidase (GPx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">Biogerontology</span> Sub-field of gerontology

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Following is a list of topics related to life extension:

<span class="mw-page-title-main">Michael Ristow</span> German medical researcher (born 1967)

Michael Ristow is a German medical researcher who has published influential articles on biochemical aspects of mitochondrial metabolism and particularly the possibly health-promoting role of reactive oxygen species in diseases like type 2 diabetes, obesity and cancer, as well as general aging due to a process called mitohormesis.

<span class="mw-page-title-main">Negligible senescence</span> Organisms that do not exhibit evidence of biological aging

Negligible senescence is a term coined by biogerontologist Caleb Finch to denote organisms that do not exhibit evidence of biological aging (senescence), such as measurable reductions in their reproductive capability, measurable functional decline, or rising death rates with age. There are many species where scientists have seen no increase in mortality after maturity. This may mean that the lifespan of the organism is so long that researchers' subjects have not yet lived up to the time when a measure of the species' longevity can be made. Turtles, for example, were once thought to lack senescence, but more extensive observations have found evidence of decreasing fitness with age.

David Gems is a British geneticist who studies the biology and genetics of ageing (biogerontology). He is Professor of Biogerontology at the Research Department of Genetics, Evolution and Environment, University College London and he is a co-founder and Research Director of the UCL Institute of Healthy Ageing. His work concerns understanding the underlying causes of aging. His research laboratory tests theories of aging and develops new ones using a short-lived animal model C. elegans.

<span class="mw-page-title-main">Methionine sulfoxide</span> Chemical compound

Methionine sulfoxide is the organic compound with the formula CH3S(O)CH2CH2CH(NH2)CO2H. It is an amino acid that occurs naturally although it is formed post-translationally.

<span class="mw-page-title-main">Biomarkers of aging</span> Type of biomarkers

Biomarkers of aging are biomarkers that could predict functional capacity at some later age better than chronological age. Stated another way, biomarkers of aging would give the true "biological age", which may be different from the chronological age.

<span class="mw-page-title-main">Selenium in biology</span> Use of Selenium by organisms

Selenium is an essential micronutrient for animals, though it is toxic in large doses. In plants, it sometimes occurs in toxic amounts as forage, e.g. locoweed. Selenium is a component of the amino acids selenocysteine and selenomethionine. In humans, selenium is a trace element nutrient that functions as cofactor for glutathione peroxidases and certain forms of thioredoxin reductase. Selenium-containing proteins are produced from inorganic selenium via the intermediacy of selenophosphate (PSeO33−).

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

This timeline lists notable events in the history of research into senescence or biological aging, including the research and development of life extension methods, brain aging delay methods and rejuvenation.

<span class="mw-page-title-main">Helmut Sies</span> German biomedical research professor

Helmut Sies is a German physician, biochemist and university professor. He was the first to demonstrate the existence of hydrogen peroxide as a normal attribute of aerobic life in 1970, and he introduced the concept of Oxidative stress in 1985. He also worked on the biological strategies of antioxidant defense and the biochemistry of nutritional antioxidants.

<span class="mw-page-title-main">Relationship between telomeres and longevity</span>

The relationship between telomeres and longevity and changing the length of telomeres is one of the new fields of research on increasing human lifespan and even human immortality. Telomeres are sequences at the ends of chromosomes that shorten with each cell division and determine the lifespan of cells. The telomere was first discovered by biologist Hermann Joseph Muller in the early 20th century. However, experiments by Elizabeth Blackburn, Carol Greider, and Jack Szostak in the 1980s led to the successful discovery of telomerase and a better understanding of telomeres.

References

  1. ↑ "Vadim Gladyshev | Brigham and Women's Hospital (BWH) | ResearchGate". ResearchGate. Retrieved 2017-11-29.
  2. ↑ Hatfield, Dolph L. (2016-07-01). "Redox Pioneer: Professor Vadim N. Gladyshev". Antioxidants & Redox Signaling. 25 (1): 1–9. doi:10.1089/ars.2015.6625. ISSN   1557-7716. PMC   4931753 . PMID   26984707.
  3. ↑ Poganik, J. R., Zhang, B., Baht, G. S., Tyshkovskiy, A., Deik, A., Kerepesi, C., ... & Gladyshev, V. N. (2022). Biological age is increased by stress and restored upon recovery. Cell Metabolism.
  4. ↑ Gladyshev, V. N. (2014). "The Free Radical Theory of Aging is Dead. Long Live the Damage Theory!". Antioxidants & Redox Signaling. 20 (4): 727–731. doi:10.1089/ars.2013.5228. PMC   3901353 . PMID   24159899.
  5. ↑ Hatfield, D. L. (2016). "Redox Pioneer: Professor Vadim N. Gladyshev". Antioxidants & Redox Signaling. 25 (1): 1–9. doi:10.1089/ars.2015.6625. PMC   4931753 . PMID   26984707.
  6. ↑ "You are what you eat: Old food shortens lifespan in animals". New Scientist. Retrieved 2017-11-29.
  7. ↑ Hatfield, Dolph L.; Gladyshev, Vadim N. (2002-06-01). "How Selenium Has Altered Our Understanding of the Genetic Code". Molecular and Cellular Biology. 22 (11): 3565–3576. doi:10.1128/MCB.22.11.3565-3576.2002. ISSN   0270-7306. PMC   133838 . PMID   11997494.
  8. ↑ "NIH Announces 2013 High-Risk, High-Reward Research Awards". National Institutes of Health (NIH). 2015-08-05. Retrieved 2017-11-29.
  9. ↑ "News from the National Academy of Sciences". 26 April 2021. Retrieved 2 July 2021. Newly elected members and their affiliations at the time of election are: ... Gladyshev, Vadim N.; professor of medicine, Harvard Medical School; and director of Redox Medicine, Brigham and Women's Hospital, Boston
  10. ↑ Gladyshev, Vadim N. (2020-07-23). "The Ground Zero of Organismal Life and Aging". Trends in Molecular Medicine. 27 (1): 11–19. doi:10.1016/j.molmed.2020.08.012. PMC   9183202 . PMID   32980264.
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