Biomedical subjects

Thomas Perls

Publications and source records attributed to Thomas Perls.

15 recordsLinked to original sources

PubMed2026

hypeR-GEM: connecting metabolite signatures to enzyme-coding genes via genome-scale metabolic models.

MOTIVATION: Enrichment analysis is a cornerstone of "omics" data interpretation, enabling researchers to connect analysis results to biological processes and generate testable hypotheses. Enrichment analysis in metabolomics poses distinct challenges for interpretation and multi-omics integration due to the lack of well-defined and consistent connections to well-curated gene-centered biological knowledge repositories. To address these challenges, we developed hypeR-GEM, a methodology and associated R package that adapts gene set enrichment analysis to metabolomics. hypeR-GEM leverages genome-scale metabolic models (GEMs) to infer reaction-based links between metabolites and enzyme-coding genes, enabling the mapping of metabolite signatures to gene signatures and their subsequent annotation via gene set enrichment analysis. RESULTS: We validated hypeR-GEM using paired metabolomics-proteomics and metabolomics-transcriptomics datasets by assessing whether genes mapped from metabolites significantly overlapped with differentially expressed proteins or transcripts. We further evaluated whether pathways enriched via hypeR-GEM-mapped genes corresponded to those derived from paired proteomic or transcriptomic data. In most datasets analyzed, both the predicted enzyme-coding genes and the associated enriched pathways showed significant concordance with independently derived omics signatures, supporting the utility and robustness of hypeR-GEM. Finally, we applied hypeR-GEM to the analysis of age-associated metabolic signatures from the New England Centenarian Study. The results revealed consistent enrichment of lipid-related pathways, aligning with the well-established role of lipid metabolism in aging, and highlighted additional pathways not captured in the metabolites' annotation, demonstrating hypeR-GEM's practical utility in a real-world use case. AVAILABILITY AND IMPLEMENTATION: The hypeR-GEM R package, documentation, and workflow examples are freely available at https://github.com/montilab/hypeR-GEM and archived at https://doi.org/10.5281/zenodo.20586748.

Metabolomics↗

PubMed2005

Scanning the beta-globin gene for mutations in large populations by denaturing capillary and gel electrophoresis.

Separation of mutant from nonmutant DNA sequences of 100 bp may be accomplished by using defined denaturing conditions of chemical denaturant and/or elevated temperature during electrophoresis on either polyacrylamide slab gels (denaturing gradient gel electrophoresis, DGGE) or capillary gels (constant denaturant capillary electrophoresis, CDCE). In analysis of mutant directly from a polymerase chain reaction (PCR) product mixture, both have detection sensitivities of approximately 1%. CDCE that facilitates an intermediate mutant enrichment step permits detection of mutants at fractions as low as 2 x 10(-6). Here we report the successful application of both approaches to scan for mutations of the human beta-globin gene (HBB) in two human population samples of approximately 5000 persons in the HBB. Using DGGE, the coding region and flanking intronic splice sites of HBB were scanned in a population of 4949 Han Chinese individuals in pool sizes of 48 individual DNA samples. Four point mutations ranging in mutant frequency from 0.5 to 0.0002 were identified. Using CDCE with a mutant enrichment step, these same sequences were scanned in a population of 5028, predominantly African-American juveniles (<9 years) as a single pooled DNA sample. Three point mutations were identified ranging in mutant frequency from 0.13 to 0.0005. This study shows that both the DGGE/small pool and the CDCE/large pool approaches offer the means to define the fine structure map of genetic variation in large population samples, and with appropriately engineered facilities to provide high throughput, should be useful in pangenomic scans to discover genes carrying casual mutations for common diseases.

Adult↗

PubMed2005

The different paths to age one hundred.

Attaining age 100 is a rare event in industrialized nations, occurring in 1 person per 10,000 in the population. Becoming a centenarian does not appear to be rare because the individual genetic or behavioral factors (such as specific genetic polymorphisms or lack of specific toxic exposures) that enable such longevity are rare, but rather because having the adequate combination of these factors is rare.

Aged, 80 and over↗

PubMed2004

Centenarians who avoid dementia.

Some researchers and many in the lay public believe the ageist myth that the older you get the sicker you get. If this were true, it would follow that most if not all centenarians should have Alzheimer's disease. Numerous centenarian studies disprove this assumption given that a small percentage ( approximately 15-25%) of centenarians are functionally cognitively intact. Among those who are not cognitively intact at 100, approximately 90% delayed the onset of clinically evident impairment at least until an average age of 92 years. Neuropsychological and neuropathological correlations thus far suggest that there are centenarians who demonstrate no evidence of neurodegenerative disease. There also appear to be centenarians who, despite the substantial presence of neuropathological markers of Alzheimer's disease, do not meet clinical criteria for having dementia, thus suggesting the existence of cognitive reserve. Centenarians are therefore of scientific interest as a human model of relative resistance to dementia.

Age Factors↗

PubMed2003

Understanding the determinants of exceptional longevity.

Centenarians represent an extreme of life expectancy. They achieve their exceptional longevity in part by lacking genetic variations linked to premature death. Pedigree studies have shown a substantial familial component in the ability to survive to extreme old age, and a recent study demonstrated a locus on chromosome 4 linked to exceptional longevity, indicating the likely existence of at least one longevity-enabling gene in humans. The children of centenarians have markedly reduced relative risks for age-related diseases, particularly heart disease, hypertension, and diabetes, and are a promising model for genetic and phenotypic studies of 1) aging slowly relative to the general population and 2) the delay of and perhaps escape from important age-related diseases. These studies and those of other mammals and lower organisms show great promise for the delineation of important environmental and genetic determinants of aging well.

Animals↗

PubMed2003

Genetics of exceptional longevity.

Centenarians exist at the extreme of life expectancy and are rare. A number of pedigree and molecular genetic studies indicate that a significant component of exceptional longevity is genetically influenced. Furthermore, the recent discovery of a genetic locus on chromosome 4 indicates the powerful potential of studying centenarians for genetic factors that significantly modulate aging and susceptibility to age-related diseases. These studies include siblings and children of centenarians. Siblings have a significantly increased propensity to achieve exceptional old age and have half the mortality risk of their birth cohort from young adulthood through extreme old age. The children of centenarians are emerging as a promising model for the genetic and phenotypic study of aging relatively slowly and the delay and perhaps escape of important age-related diseases.

Aged↗

PubMed2003

Anti-aging teleconference: what is anti-aging medicine?

The concepts of "anti-aging" and "anti-aging medicine" in particular are hotly debated now, both in the mass media and among some researchers. This paper represents an open discussion of anti-aging terms and related ideas by nine leading experts in the field of aging studies, and it describes in detail the arguments presented by both supporters and opponents of these concepts. Candid exchange of opinions makes it clear that more efforts are required before a consensus on these issues can be reached. The paper also presents evidence that the term "anti-aging" is routinely used now in scientific literature as a legitimate scientific term, including even the titles of publications in reputable scientific journals, written by established researchers.

Aging↗

PubMed2003

Morbidity profiles of centenarians: survivors, delayers, and escapers.

BACKGROUND: The compression of morbidity hypothesis predicts that, in order to achieve their extreme old age, centenarians markedly delay or even escape diseases that would otherwise be lethal at younger ages. Phenotypic studies have not adequately characterized the prevalence and timing of age-related illnesses among those who achieve exceptional old age. Thus, we conducted a retrospective cohort study of centenarians to explore the timing of such diseases among centenarians. METHODS: Health history questionnaires were completed by 424 centenarians (aged 97-119 years) or their proxies. Lifetime (to-date) diagnoses of 10 major lethal illnesses (hypertension, heart disease, diabetes, stroke, nonskin cancer, skin cancer, osteoporosis, thyroid condition, Parkinson's disease, and chronic obstructive pulmonary disease) and one ocular disease (cataracts) that befall the elderly population, approximate age of diagnosis, level of alcohol and tobacco use, and presence or absence of cognitive impairment were assessed. Because of the retrospective nature of the study, the typically imprecise age of onset of cognitive impairment negated the ability to include age of onset of cognitive impairment in this aspect of the analyses. RESULTS: Examining the ages of onset for the 10 age-associated diseases and excluding cognitive impairment, we found that the centenarians fit into three morbidity profiles-Survivors, Delayers, and Escapers. 24% of male subjects and 43% of female subjects fit the Survivor profile, or those who had a diagnosis of an age-associated illness prior to the age of 80. Delayers were individuals who delayed the onset of age-associated illness until at least the age of 80, and 44% of male and 42% of female subjects fit this profile. Escapers were individuals who attained their 100th year of life without the diagnosis of common age-associated illnesses, and 32% of male and 15% of female subjects fit the Escaper profile. When examining only the most lethal diseases of the elderly population, heart disease, nonskin cancer, and stroke, we found that 87% of male and 83% of female subjects delayed or escaped these diseases. Subjects with and without cognitive impairment did not differ in terms of the profile to which they belonged. CONCLUSIONS: These results suggest there may be multiple routes to achieving exceptional longevity and that there are sex differences according to which route is taken. These routes represent different phenotypes and thus likely different genotypes of centenarians. The identification of three types of centenarians, Survivors, Delayers, and Escapers, provides direction for future study into the factors that determine exceptional longevity.

Age of Onset↗

PubMed2002

What does it take to live to 100?

Centenarians disprove the ageist myth "the older you get, the sicker you get"; they live 90-95% of their very long lives in excellent health, only to experience illnesses in the very last few years of their lives. Thus, it appears that in order to live to 100, one must age relatively slowly and markedly delay and/or escape age-associated diseases. How they achieve such a survival advantage is still a mystery though it is becoming increasingly clear that a substantial genetic advantage plays a role in their ability to live 20-25 years beyond average life expectancy. Current genetic studies of centenarian sibships may yield the identity of some of these genes in the near future. Identifying such genes may yield new information about how people age differently and what modulates differences in susceptibilities to various diseases associated with aging.

Animals↗

PubMed2002

The genetics of aging.

Once thought to be an extremely complex conundrum of weak genetic and environmental effects, exceptional longevity is beginning to yield genetic findings. Numerous lower organism and mammalian models demonstrate genetic mutations that increase life-span markedly. These variations, some of them evolutionarily conserved, inform us about biochemical pathways that significantly impact upon longevity. Centenarian studies have also proven useful as they are a cohort that, relative to younger age groups, lacks genotypes linked to age-related lethal diseases and premature mortality. Pedigree studies have demonstrated a significant familial component to the ability to survive to extreme old age and a recent study demonstrates a locus on chromosome 4 linked to exceptional longevity indicating the likely existence of at least one longevity enabling gene in humans. Thus, a number of laboratories are making substantial and exciting strides in the understanding of the genetics of aging and longevity which should lead to the discovery of genes and ultimately drugs that slow down the aging process and facilitate people's ability to delay and perhaps escape age-associated diseases.

Aging↗

PubMed2002

The genetics of exceptional human longevity.

There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human's ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health. To live beyond the octogenarian years, life-span experiments in lower organisms and mammals and population and molecular genetic studies of centenarian sibships suggest that genetic factors play an important role in exceptional longevity. These factors are likely to influence basic mechanisms of aging, which in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease, and having variations that confer disease resistance (longevity enabling genes), are probably both important to such a remarkable survival advantage. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

Aged↗

PubMed2002

Genetic and environmental influences on exceptional longevity and the AGE nomogram.

To live beyond the octogenarian years, population and molecular genetic studies of centenarian sibships indicate that genetic factors play an increasingly important role as the limit of life span is approached. These factors are likely to influence basic mechanisms of aging that in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease as well as having variations that confer disease resistance (longevity enabling genes) are probably both important to achieving exceptional old age. The AGE (aging, genetics, environment) nomogram is introduced as an illustrative construct for understanding the influence of environmental and genetic factors on survival to various ages, depending on variations in the hypothesized relative importance of genes and environment to longevity. The rapid rise in the incidence of centenarians could indicate that many more people than we originally thought have the optimal set of genetic factors necessary to get to 100 and beyond. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

Aged↗

PubMed2002

The genetics of aging-- implications for pharmacogenomics.

Lifespan experiments of lower organisms and mammals along with recent studies of centenarians are making inroads into delineating genetic factors that determine the ability to achieve exceptional longevity. These models may be helpful for the discovery of both longevity-enabling genes as well as genes associated with increased propensity to develop specific diseases. Both academic and commercial laboratories are putting substantial resources into discovering such genes in order to better understand the genetic and environmental underpinnings of how some people age more slowly than others and markedly delay or even escape age-associated diseases.

Aged↗

PubMedDate not supplied

The genetics of exceptional human longevity.

How we age as individuals is no doubt a complex interaction of genetic and environmental factors. Studies of certain populations with optimal environments and health-related behaviors, as well as twin studies, suggest that the average set of genetic variations should facilitate the average person's ability to live to around age 85. Average life expectancies are lower than this because we generally fight survival advantage with bad health habits that can lead to premature aging, chronic illness, and death at a significantly younger age. Centenarians on the other hand live 15-25 years beyond what the average collection of us are able to achieve. Many of them have a history of aging relatively slowly, and either markedly delaying or even escaping lethal diseases associated with aging (Alzheimer's disease, stroke, cancer, cardiovascular disease, and diabetes). In order to live to such old age, centenarians are less likely to have genetic and environmental exposures that would cause at least lethal diseases at younger ages. Demographic selection is the drop out within a cohort, of genotypes linked to age-related lethal diseases and premature mortality as the cohort achieves older and older age. The result is a very old cohort that lacks these genotypes relative to younger age groups. Recent pedigree and molecular genetic studies indicate that scientists can use this selection to their advantage in discerning genotypes that play important roles in delaying or escaping diseases such as Alzheimer's disease, and in slowing the aging process.

Adult↗

PubMedDate not supplied

Dementia-free centenarians.

BACKGROUND: A small percentage of centenarians, about 15-25%, are functionally cognitively intact. Among those who are not cognitively intact at 100, approximately 90% delayed the onset of clinically evident impairment at least until the average age of 92 yr. OBJECTIVE: To review current and past findings related to the prevalence and incidence of dementia amongst the exceptionally long-lived. METHODS: Findings from the various centenarian studies, world-wide, are reviewed. RESULTS: Neuropsychological and neuropathological correlations thus far suggest that there are centenarians who demonstrate no evidence of neurodegenerative disease. There also appear to be centenarians who despite the substantial presence of neuropathological markers of Alzheimer's disease did not meet clinical criteria for having dementia, thus suggesting the existence of cognitive reserve. Epigenic studies suggest a significant familial component to these survival advantages. CONCLUSION: Centenarians are of scientific interest as a human model of relative resistance to dementia.

Aged↗