Summary of Article Have You Come a Long Way Baby?
When Rozalyn Anderson asked me to contribute an article on my reflections of the field of aging, I immediately idea of how much the field had changed since I initiated my research at Illinois Land Academy in 1971. This was the same year that the White House Conference on Crumbling recommended the creation of the National Institute on Aging (NIA). Before the institution of NIA, aging inquiry was funded through the National Institute for Mental Wellness. Although President Richard Nixon vetoed the bill creating NIA in 1973, Congress in 1974 granted say-so to form NIA, which would "provide leadership in crumbling enquiry, training, health data dissemination, and other programs relevant to aging and older people" (taken from NIA website). Because in that location were no report sections for aging, aging grants were reviewed by study sections with no expertise and by reviewers with little to no interest in aging. At this fourth dimension, many researchers exterior of aging viewed aging every bit a difficult if non pointless trouble to study. I saw this immediate at a meeting NIA organized in the mid-1970s where various leaders in aging described their enquiry to a panel of leading researchers exterior of aging. I remember vividly when, Ira Wool, who was internationally recognized for his research on characterizing the ribosome, told anybody at the meeting, including NIA director and staff, that NIA should be supporting basic biological research and not crumbling research because aging simply occurs randomly over time; it was pointless to report aging because no biological procedure was involved. I thought at the time, "my God how am I ever going to get funded with report section reviewers who have such a bias." Fortunately, not all reviewers had such a bias. In the fall of 2003, 2 study sections were initiated that were designed to review grants that focused on crumbling: Cellular Mechanisms in Aging and Development (CMAD) and Aging Systems and Elderliness (ASG). Ii years later, these study sections were officially chartered every bit members of the NIH report sections.
The major problem that confronted researchers studying aging in the 1970s was that our research was primarily descriptive. Most of usa were studying the result of crumbling on some biological process rather than straight testing mechanisms. While it was important to define how aging was affecting various pathways and molecular and physiological processes because so fiddling was known at this time, this research was not mechanistic and, therefore, non highly reviewed. The lack of interventions that retarded aging that could be used to test mechanisms was the chief problem that faced investigators studying aging in the 1970s and 1980s. In this article, I have highlighted those intervention studies, which I feel played a key role catalyzing the dramatic growth of biological research in aging and changed our perception of how crumbling occurs at the molecular level.
The Era of Caloric Brake
In 1970, the only intervention known to increase life span was caloric restriction (CR), which had been discovered by McCay in 1935 (Effigy 1A) (ane). Although numerous studies over the following 3 decades showed that CR increased the life bridge of rats and mice (ii,3), there were concerns even in the aging customs in the 1970s equally to whether CR increased life span past retarding aging. During the 1970s and 1980s, research atomic number 82 by Edward Masoro at the University of Texas Wellness Science Heart with rats and Roy Walford at the University of California at Los Angeles with mice demonstrated conclusively to the research community that CR had a major impact on aging, for example, it prevented/delayed the incidence of most age-related diseases and pathologies in rodents and improved a broad variety of physiological processes that declined with age. It is impossible to overstate how important the enquiry past Masoro and Walford was to the field of aging because their research demonstrated conclusively for the first fourth dimension that crumbling could be delayed in a mammal resulting in a more than youthful phenotype. Because of their research, CR became the aureate standard used for retarding aging. In add-on, this research opened the door to the starting time studies to test potential mechanisms that could play a role in aging by studying the pathways adulterate past CR.
Figure i.
The effect of some of the major aging interventions on the life spans of rodents and invertebrates. Panel A: The life span of male rats fed a restricted diet or ad libitum. Data taken from McCay et al (1). Console B: The life bridge of the age-1 (hx546) mutant of nematodes. Information taken from Friedman and Johnson (iv). Panel C: The life span of yeast expressing the RAS gene. Data taken from Chen et al (5). Panel D: The life bridge of male Ames dwarf (df/df) mice. Data taken from Bartke et al (6). Panels East and F: The life spans of male and female mice fed rapamycin. Data taken from Harrison et al (7).
Figure one.
The result of some of the major aging interventions on the life spans of rodents and invertebrates. Panel A: The life span of male rats fed a restricted diet or advert libitum. Data taken from McCay et al (1). Panel B: The life span of the age-ane (hx546) mutant of nematodes. Information taken from Friedman and Johnson (iv). Panel C: The life bridge of yeast expressing the RAS gene. Data taken from Chen et al (5). Panel D: The life span of male Ames dwarf (df/df) mice. Data taken from Bartke et al (6). Panels E and F: The life spans of male person and female mice fed rapamycin. Data taken from Harrison et al (vii).
The inquiry of Masoro and Walford sparked the interest of many new investigators to study CR in rodents, such equally myself, Rick Weindruch, Don Ingram, George Roth, Jim Nelson, Dave Harrison, Brian Merry, Roger McCarter, Walter Ward, B. P. Yu, and Gab Fernandes, to name a few. The 1983 Gordon Conference on the Biology of Aging brought together the leaders in CR for the showtime fourth dimension (Figure 2). Enquiry in the 1980s and 1990s demonstrated that CR prevented/attenuated changes that occurred in well-nigh every pathway or process that was contradistinct past historic period. Therefore, the hope that CR would aid identify a specific pathway or mechanism responsible for aging was non achieved.
Figure 2.
The 1983 Gordon Research Briefing on the Biology of Aging. The Briefing was chaired past Edward Masoro and held at Holderness School. Information technology was the first major national coming together to focus on caloric restriction. The investigators studying caloric restriction (left to right starting at the bottom) are: ane—Rick Weindruck, ii—Roy Walford, 3—Dave Harrison, iv—Ed Masoro, five—George Roth, six—Gabe Fernandes, 7—Caleb "Tuck" Finch, 8—Dike Kalu, 9—Jim Nelson, 10—Don Ingram, eleven—Jim Joseph, 12—Roger McCarter, 13—John Holloszy, 14—Arlan Richardson, 15—Jerry Herlihy, 16—B. P. Yu, 17—Helen Bertrand, and xviii—Walter Ward.
Effigy two.
The 1983 Gordon Research Conference on the Biological science of Aging. The Conference was chaired by Edward Masoro and held at Holderness School. It was the first major national meeting to focus on caloric restriction. The investigators studying caloric restriction (left to right starting at the lesser) are: 1—Rick Weindruck, 2—Roy Walford, iii—Dave Harrison, iv—Ed Masoro, 5—George Roth, 6—Gabe Fernandes, 7—Caleb "Tuck" Finch, viii—Dike Kalu, 9—Jim Nelson, x—Don Ingram, 11—Jim Joseph, 12—Roger McCarter, 13—John Holloszy, 14—Arlan Richardson, 15—Jerry Herlihy, 16—B. P. Yu, 17—Helen Bertrand, and eighteen—Walter Ward.
In the late 1980s, two groups initiated studies testing the long-term outcome of CR in rhesus monkeys: Rick Weindruch and Joe Kemnitz at the University of Wisconsin and George Roth and Don Ingram at the NIA Intramural Research Plan. These studies were conducted to a big extent considering researchers at the time questioned the relevance of CR to long-lived species such as humans. Over the next 3 decades, the enquiry generated past these 2 groups (which later included Rozalyn Anderson and Ricki Colman at the Academy of Wisconsin and Marking Lane and Julie Mattison at NIA) showed that CR improved the health (8) and longevity (9) of rhesus monkeys much every bit it did in rodents. To date, CR is the only crumbling intervention that has been shown to retard aging in a nonhuman primate, demonstrating that interventions that increased life span and retarded aging in rodents take the potential to also work in long-lived species such as primates.
In 2001, NIA initiated the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study, which was the first clinical trial to study the effects of prolonged CR on healthy homo participants (10). It was conducted at 3 sites: Pennington Biomedical Inquiry Centre directed by Eric Ravussin and Donald Williamson, Tufts University directed past Susan Roberts, and Washington University directed past John Holloszy and Luigi Fontana. The report demonstrated the feasibility of sustained human CR (for 2 years) and showed improvement of predictors of longevity and cardiometabolic take a chance factors (xi,12). Thus, the outcome of CR on aging appears to translate from rodents to humans, demonstrating the usefulness of rodents in studying interventions of aging.
The Era of Genetic Manipulations in Aging
In the 1980s, a major shift in aging research occurred that had a profound effect on the field, the employ of invertebrate models to study aging. Drosophila (Drosophila melanogaster) had been used in crumbling research to a limited extent in the 1960s and 1970s; however, most investigators studying aging at the time were skeptical almost the relevance of findings in Drosophila to mammals. The recognition in the late 1970s that organisms from yeast to humans employed similar molecular mechanisms to regulate almost biological processes led to the broad use of invertebrates in biomedical research. The ability to genetically manipulate invertebrates combined with their short life bridge, made them particularly attractive for aging research. Tom Johnson and Mike Jazwinski were the beginning advocates for using nematodes (Caenorhabditis elegans) and yeast (Saccharomyces cerevisiae), respectively, in crumbling inquiry.
The initial studies with invertebrates in the 1980s focused on determining if it was possible to select for long-lived invertebrates. Michael Rose (13) and Leo Luckinbill and Bob Arking (xiv) obtained long-lived Drosophila by selecting female flies for late-life reproduction. These studies demonstrated that long-life and delayed senescence were genetically regulated; however, as with CR, studies with the long-lived strains of Drosophila did not lead to any major insight into the molecular pathways underlying aging because the long-lived flies showed a broad range of changes. Michael Klass took another approach to generating long-lived nematodes; he treated nematodes with a mutagen and selected for long-lived mutants. At the time, it was believed that to increase the life span in an animal, you would have to improved fitness/role. Therefore, most investigators in aging were skeptical as to whether a loss of part mutation, as one would obtain past treating nematodes with a mutagen, would yield longevity mutants. However, Klass obtained several mutants that appeared to be long-lived (xv). It was assumed that these long-lived mutants had mutations in several genes, which lead to their increased longevity. Still, when Tom Johnson outcrossed some of these mutants, he discovered a long-lived mutant with a recessive mutant in one gene, which he named historic period-1. The mutation increased life span 40% to 65% (Figure 1B) (four). Subsequently, he showed that the age-i mutation reduced the exponential increment in mortality rate, demonstrating that the age-1 mutants were aging more slowly (16).
Tom Johnson's discovery had an enormous impact on the field because information technology demonstrated that i gene could influence aging, which provided the first model that could be used to direct identify a pathway(s) involved in aging. Considering of Tom's research, Cynthia Kenyon became interested in using nematodes to study the genetics of aging (17). Her grouping screened for long-lived nematode mutants and in 1993 reported another long-lived mutant, daf-ii (18). Subsequently, Gary Ruvkin'due south grouping showed that the age-1 gene encoded a phosphatidylinositol 3-kinase (19), and daf-2 encoded the nematode homologue of the man insulin and IGF-1 receptors (twenty), which activates downstream PI3 kinase pathways. Thus, the insulin/IGF-1 pathway was the starting time pathway to be shown to play a role in aging in any organism.
Shortly after Tom Johnson had reported that mutations in the historic period-ane factor increased the life span of nematodes, Mike Jazwinski reported that overexpressing the RAS gene increased the replicative life span of yeast (Figure 1C) (5). Overexpressing RAS appeared to increase the longevity of yeast by maintaining homeostasis through metabolic control and resistance to stress (21). Interestingly, some aspects of metabolic control in yeast induced by RAS resembled the metabolic consequences seen in nematodes and Drosophila selected for extended longevity and CR in rodents. Later, Lenny Guarante's group identified long-lived yeast with mutations in the gene encoding SIR4 (22). Based on the reports in nematodes and yeast, investigators began looking for genes or mutations that pb to increased life span in Drosophila. The initial studies with Drosophila showing that the overexpression of EF-1α (23) or catalase and Cu/Zn-superoxide dismutase (24) increased the life span of Drosophila suffered from poor controls and were not replicated. In 1998, Seymour Benzer'due south group reported that mutations in the mth gene, which is homologous to M poly peptide-coupled receptors, increased the life bridge of Drosophila (25). Two years later, Steve Helfand'due south group discovered that mutations in the Indy gene near doubled the life span of Drosophila (6). The Indy gene coded for a cotransporter cistron that is closely related to the mammalian sodium dicarboxylate cotransporter, and it was argued that these mutants create a metabolic state that mimics CR.
By the early 1990s, information technology was apparent that life span could be extended dramatically in nematodes and yeast by a single cistron. The major question at this time was whether single gene mutations could increase the life bridge of mammals or was this unique to invertebrates. In 1996, Andrzej Bartke's group made the seminal discovery that Ames dwarf mice (df/df) live significantly longer that their normal siblings (Figure 1D) (26). The Ames dwarf mice accept a mutation in the Prop-1 gene, which results in a failure of somatotropes and lacotropes to differentiate, leading to mice deficient in growth hormone, prolactin, and thyroid stimulation hormone. This discovery was even more surprising because the aging customs believed that dwarf mice were a model of rapid crumbling. Dwarf mice initially had been reported to be curt-lived (27) and growth hormone product was shown to decreased with age (28). In 2001, Dave Harrison's group reported that Snell dwarf mice, which have a mutation in the Pit-1 gene, as well showed an increase in life span (29). Afterwards, it has been shown that mutations in growth hormone receptor, growth hormone-releasing hormone, and growth hormone-releasing hormone receptor increased the life bridge of mice (for review, meet (30)). These data indicated that the growth hormone/IGF-1 pathway plays an important role in mammalian crumbling.
The research in the 1990s demonstrating that mutations lead to increased life bridge prompted investigators to report how prevalent longevity gene mutations were in invertebrates. Gary Ruvkin's group used a systematic RNAi screen to identify gene inactivation mutations that increment life span. In 2003, they reported that RNAi inactivation of ~2% of the of 5690 genes analyzed atomic number 82 to a significant increase in life bridge of five% to thirty%; 15% of these mutants were specific for mitochondrial function (31). The laboratories of Matt Kaeberlein and Brian Kennedy as well plant that ~2% of the 564 single-factor deletion strains of yeast tested showed an increment in replicative life span, with i of these genes encoding components of the TOR (target of rapamycin) signaling pathway (32). Based on their information, they predicted that 100 to 120 "crumbling genes" were potentially possible in yeast (7). Currently, more 800 genes accept been reported to increase the life span of nematodes and over l genes have been reported to increase the life span of mice (33).
Era of Pharmacological and Pharmaceutical Interventions in Aging—The Crumbling Intervention Testing Program
It is impossible to overstate how important the ability to genetically manipulate invertebrates and mice was to the advancement of our understanding of potential mechanisms responsible for crumbling. However, translating these discoveries to pharmacological/pharmaceutical interventions that potentially could be taken to humans was limited at the beginning of the 21st century. The establishment of the NIA-funded Intervention Testing Plan (ITP) in 2004 was a major step toward identifying pharmacological/pharmaceutical interventions in aging. Don Ingram came upwardly with the concept of a program to test longevity-increasing interventions in mice, and in 1997, he proposed such a program to the Board of Scientific Councilors of the Intramural NIA Programme. Working with Huber Warner, who was the Director of the Partitioning of Crumbling Biology at NIA, they organized a workshop, which was held in Texas in 1999, to discuss the concept of such a plan. As role of the workshop, I call up that all of the participants were very positive about need for a program that would rigorously test the ability of compounds to increase the life bridge of mice. At the time, there were a number of "antiaging" compounds being promoted in the news media, for example, DHEA (dehydro-3-epiandrosterone) and melatonin, for which the life-bridge information were weak. While there was stiff support for the program, the general consensus was that it was not realistic to argue that the chief goal of the program was to identify compounds that increase life span because the research community more often than not felt it was unlikely that any one compound would accept a pregnant impact on crumbling/life bridge. Rather, it was felt that it would exist ameliorate to argue that such a plan was needed to test rigorously whether compounds had a significant impact on life bridge by an independent group of investigators who had no involvement in the compounds being studied. The workshop recommended that the life span should be tested at three sites in both male and female UM-HET3 mice, a line of genetically heterogeneous mice that had been recently adult by Rich Miller. As a result of the workshop, Huber Warner presented the concept of the ITP to the annual NIA retreat in 1999: "at first, Dr. Ingram and I could convince few if any of our NIA colleagues that this was a worthwhile enterprise. Notwithstanding, we tried again the following year, once more with only express success, merely on third effort, Dr. Hodes gave us the green light..." (34). In 2003, a request for applications (RFA) was issued, and 3 sites were funded in 2004: the Jackson Laboratory led by Dave Harrison, the University of Michigan, led by Rich Miller, and the Academy of Texas Health Science Centre at San Antonio, led by Randy Stiff. Since 2004, the ITP has been testing the ability of compounds to increase the life span of mice as a mensurate of a compound's ability to retard aging. These compounds were proposed to the ITP by investigators studying aging.
A major quantum occurred in 2009, when the ITP reported that rapamycin significantly increased the life bridge of both male and female mice (Figure 1E and F) (35). Dave Abrupt had proposed testing rapamycin to the ITP in 2004. He was a very creative molecular biologist studying cancer at the University of Texas Health Science Center in San Antonio and was part of a program project I directed in 1998–2003 that used transgenic and knockout mouse models to report CR. Dave became interested how reducing calories could delayed aging at the molecular level. Effectually 2000, he came up with the thought that TOR might be the key to CR considering it was a nutrient sensor. Based on data from Michael Hall's grouping (36), which showed rapamycin mimicked the starvation phenotype in yeast past inhibiting TOR, Dave hypothesized that the reducing TOR signaling past feeding mice rapamycin would lead to increased life span. He was not able to obtain funding for this study because it was viewed equally very risky and because there were no data on treating mice long term with rapamycin. The cursory report in 2003 by Vellai et al (37) showing that TOR deficiency doubled the life span of nematodes provided Dave with the back up he needed to convince the ITP to test rapamycin.
In conducting the rapamycin study, the ITP was faced with the problem of how to administer rapamycin to the mice. All of the previous studies injected rapamycin intraperitoneally, which was non realistic to do in a life-span experiment. However, ~85% of the rapamycin was degraded in preparing the diet containing rapamycin. Therefore, Randy Strong came up with the novel concept of encapsulating rapamycin with a material developed by the Southwest Research Institute (San Antonio) that would protect rapamycin from deposition in the diet as well the stomach and would exist solubilized by the bones pH in the modest intestine, thereby delivering rapamycin to the animal. The ITP had generated a cohort of UM-HET3 mice then they could beginning feeding rapamycin at iv months of age. Even so, the mice were ~nineteen months of age when the rapamycin-containing diet became available. There was a give-and-take of whether to study the result of treating these mice with rapamycin considering at this the time the existing data on CR indicated that an intervention had to be implemented relatively early in life for information technology to be successful. Fortunately, the ITP decided to feed the old mice rapamycin and the rest is history. The ITP not only discovered the kickoff pharmaceutical intervention to increase life span in a mammal, just as of import, they demonstrated for the offset time that an intervention could increase the life span of mice when initiated later on in life. The editors of Science selected this discovery as one of the top x scientific breakthroughs in 2009 (Scientific discipline 326, 1602–1603, 2009). This was the first time a discovery in aging was recognized by the scientific community every bit a major breakthrough in scientific discipline. Two years after the discovery that rapamycin increased the life span of mice, a 2nd discovery in crumbling was selected by Science equally one of the top 10 scientific breakthroughs (Science 334, 1635, 2011). van Deursen's group discovered that genetically removing senescent cells postponed age-related disease in mice (38). Currently, fifteen studies have shown that rapamycin increases the life span of various strains of mice (33,39), demonstrating the robustness of the event of rapamycin on life span of mice. Rapamycin also been shown to benumb many age-related conditions, including cancer, neurodegeneration (including Alzheimer'south disease), and cardiac disease/part (39).
Translating Bones Biomedical Research to the Dispensary
For the starting time fourth dimension in human history, nosotros were in a position to test aging interventions in humans that have been rigorously validated to increase life span and retard aging in creature models. However, several hurdles needed to be overcome earlier this was possible. Kickoff, a protocol for testing the ability of a drug to affect aging in humans needed to be adult considering it is impractical to practise a life-span study to demonstrate the efficacy of a compound in humans as is washed with invertebrates and mice. The outset stride in developing such a protocol was initiated in 2013 when Steve Austad, Jim Kirkland, and Nir Barzilai received a R24 grant from NIA to join experts in the biology of crumbling and clinical geriatrics to discuss how to deport a clinical trial that targets aging in humans. Every bit a result of this grant, the showtime clinical, geroscience-guided trial, TAME (Targeting Crumbling and Metformin) was proposed. Metformin was chosen as the outset drug to text because it had been safely used to treat diabetes for over 60 years with minimal side effects, it reduced the incidence of many historic period-related diseases, and contradistinct several pathways known to exist involved in crumbling (eg, insulin levels, IGF-1 signaling, and mTOR signaling) (40). With Nir Barzilai leading the effort, the TAME trail received FDA blessing in 2015 and funding at the terminate of 2019. Ironically, the funds for clinical trial of TAME came from private sources rather than NIA/NIH. TAME is a randomized clinical trial involving xiv institutions with over 3000 participants. The trial will follow the incidence of age-related diseases and a panel of 9 blood-based biomarkers (41) in participants receiving metformin or a placebo control. In the next decade, nosotros should know if the unique protocol developed for the TAME clinical trial tin be used for testing the effect of other drugs on aging in humans.
Another trouble confronting aging researchers is how to have compounds that the ITP has constitute to piece of work in mice to humans. In developing the ITP, we never guessed that it would exist as successful as it has been; therefore, there has been no serious discussion to appointment as to what steps should be used when taking a compound from mice to humans. One cannot presume that pharmacological interventions in mice volition automatically interpret to humans, for example, but about i in 10 successful mouse cancer interventions ever makes it to the clinic and none of the 300+ mouse interventions in Alzheimer's disease has proven constructive in humans. Due to the cost in time and money of homo clinical trials, it is critical that that NIA develop a plan/program to exam the translatability of compounds identified by the ITP in mice, for instance, decide the result of the compounds on aging in other species likewise as screening for potential side effects.
Even in the absence of a such a programme, several investigators have begun testing the translatability of the ITP data. Currently, Daniel Promislow and Matt Kaeberlein at the Academy of Washington are studying the upshot of rapamycin on aging in dogs as office of their Canis familiaris Aging Project (42), and Adam Salmon is funded to study the effect of rapamycin on crumbling in the common marmoset (43). Steve Austad and I have proposed using rats equally a follow up to the ITP studies with mice. Rats differ from mice in a variety of physiological parameters making them more similar to humans in many aspects than mice, including finish-of-life pathology and drug toxicity (44). A major advantage to using the rat is their life span is relatively short (like to mice), for example, much shorter than that of dogs or nonhuman primate models, making them an ideal model to quickly test the antiaging furnishings of compounds identified past ITP.
Summary
Over the past 50 years, basic biomedical enquiry in aging has gone from a relatively obscure area of research to one of the hottest areas of science resulting in major discoveries in scientific discipline in 2009 and 2011 (summarized in Figure3). In 1970, it was more often than not believed that it would be hard to intervene in aging. However, we now know that mutations in hundreds of genes can increase the life bridge of invertebrates and dozens of genes increase the life span of mice. In addition, the ITP has been much more successful than originally believed possible. Currently, the ITP has identified four compounds that have consistently shown over a 10% increment in the life span of mice: rapamycin, 17α-estradiol, acarbose, and nordihydroguaiaretic acid. Three other compounds (aspirin, protandim, and glycine) evidence a modest (<x%) just pregnant increase in life span.
Figure three.
Summary of the major discoveries and developments in the biology of aging in the past 50 years.
Figure 3.
Summary of the major discoveries and developments in the biology of aging in the by 50 years.
In closing, I experience information technology is important to recognize 2 unsung heroes who played a major role in the dramatic advancements in biological research in aging over the past 25 years: Huber Warner and Felipe Sierra. They served as directors of the Division of Crumbling Biology at NIA from 1989 to 2020. Based on input from the research community, they were responsible for steering the inquiry funded by the Sectionalization of Biology on Aging through its most productive era to appointment. Huber was responsible for the Division's push button to identify specific genes involved in aging (the Longevity Assurance Genes, LAG, initiative) as well as the evolution of the ITP, every bit described higher up. Felipe was single-handedly responsible for the development of a new field in aging: Geroscience, which is the study of mechanisms through which changes in cellular/tissue function with age contribute to the onset and progression of specific diseases. Previously, most researchers studying aging went to great lengths not to study old animals when they had major diseases, such as cancer. They wanted to study "pure" aging in the absence of disease. Conversely, Institutes studying major historic period-related diseases ignored the role aging played in these diseases. Felipe was able to convince other Institutes at NIH almost the importance of crumbling in the etiology of the historic period-related diseases they were studying. His efforts led to the cosmos of the Trans-NIH GeroScience Interest Group (GSIG), which focuses on exploring the intersection between aging biology and the biology of diseases. The GSIG currently involves over twenty NIH Institutes and has led to increased funding for basic research in aging through RFAs from Institutes other than the NIA, interested in exploring the role of aging in the particular diseases each Institute is studying.
Arlan Richardson received his PhD in chemistry from Oklahoma State University and did his postdoctoral preparation at the University of Minnesota. In 1971, he joined the faculty at Illinois State University and began his enquiry studying the role of gene expression in aging and caloric restriction in rats. His group was the first to evidence that caloric restriction altered the expression of specific genes through changes in transcription factors. In 1990, he joined the faculty at the University of Texas Wellness Science Middle at San Antonio where he became the Founding-Director of the Barshop Institute on Longevity and Crumbling Studies in 1995. At San Antonio, Dr. Richardson changed his focus from rats to mice to accept advantage of the ability to genetically modify mice. With Dr. Holly Van Remmen, initially a postdoctoral beau in his laboratory and after a collaborator, he directly tested the function of oxidative stress in aging using various transgenic and knockout mouse models with alterations in the antioxidant defense arrangement to reduce or increase oxidative stress. Data generated over xv years with multiple genetic models demonstrated that altering the level of oxidative damage had no significant impact on the life span of mice, calling into question the role oxidative stress has in aging. In 2013, Dr. Richardson joined the University of Oklahoma Health Sciences Middle where he continues to report caloric restriction. Dr. Richardson served as President of the American Aging Association and the Gerontological Society of America. In improver, he has received the Robert W. Kleemeier Award from the Gerontological Order of America, the Harman Inquiry Accolade from the American Aging Association, the Irving Wright Award of Distinction in Aging Research from the American Federation for Crumbling Research, and the Lord Cohen Medal for Services to Gerontology from the British Society for Enquiry on Ageing.
Acknowledgments
I want to thank Drs. Donald Ingram, Felipe Sierra, Holly Van Remmen, and Michal Jazwinski for their helpful comments when reviewing the manuscript.
Funding
In writing this manuscript, the author was supported by a Senior Career Enquiry Award from the Section of Veterans Affairs.
Disharmonize of Interest
None declared.
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