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The purpose of this early contribution to the new Fellows Forum of this pioneering journal for what is now called Geroscience is to provide an example of how the author's interest in using the emerging tools of human genetics has led to strong support for one of the hallmarks of aging-Genomic Instability. We shall also briefly review our emerging interests in the genetic analysis of what we have called Antigeroid Syndromes. While there has been significant progress in that direction via genetic studies of centenarians, the search for genetic pathways that make individuals unusually resistant or resilient to the ravages of specific geriatric disorders has been comparatively neglected. We refer to these disorders as Unimodal Antigeroid Syndromes. It is our hope that our young colleagues will consider research efforts in that direction. [ABSTRACT FROM AUTHOR]

Cell-to-cell variation in gene expression increases among homologous cells within multiple tissues during aging. We call this phenomenon variegated gene expression (VGE). Long, healthy life requires robust and coordinated gene expression. We posit that nature may have evolved VGE as a bet-hedging mechanism to protect reproductively active populations. The price we may pay is accelerated aging. That hypothesis will require the demonstration that genetic loci are capable of modulating degrees of VGE. While loci controlling VGE in yeast and genes controlling interindividual variation in gene expression in Caenorhabditis elegans have been identified, there has been no compelling evidence for the role of specific genetic loci in modulations of VGE of specific targets in humans. With the assistance of a core facility, we used a customized library of siRNA constructs to screen 1,195 human genes to identify loci contributing to the control of VGE of a gene with relevance to the biology of aging. We identified approximately 50 loci controlling VGE of the prolongevity gene, SIRT1. Because of its partial homology to FOXO3A, a variant of which is enriched in centenarians, our laboratory independently confirmed that the knockdown of FOXF2 greatly diminished VGE of SIRT1 but had little impact upon the VGE of WRN. While the role of these VGE-altering genes on aging in vivo remains to be determined, we hypothesize that some of these genes can be targeted to increase functionality during aging. [ABSTRACT FROM AUTHOR]

Background Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality. [ABSTRACT FROM AUTHOR]

Graph One of the pioneers of modern geroscience, George M. Martin, has left us. This global cohort of trainees and junior colleagues loved and revered George, and their successes were always a great source of satisfaction to George. Together, George and Julie hosted scientists from around the globe and nurtured the careers of countless young investigators. [Extracted from the article]

Background: early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability. Objective: to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality. Design: population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals. Participants: genetic data are available for 1,805 individuals. Methods: each of six genotypes of three common alleles of the APOE locus (ε2, ε3 and ε4) was tested on the association with a disability index or mortality. Results: APOE ε3/ε3 genotype significantly decreases odds ratio (OR) for IADL disability in males [OR = 0.48; 95% Confidence Interval (Cl) 0.31-0.76] while it exhibits no association in females. The OR for ADL disability is 0.19 (CI 0.04-0.99) for ε4/ε4 female carriers. The ε2/ε3 genotype increases the chances of TADL disability for males (OR = 2.33; CI 1.28-4.25). No significant association between APOE polymorphism and mortality was found. A surprising observation was that ε4/ε4 female carriers have a 5.3 times lower chance of having ADL disability than non-ε4/ε4-carriers. Conclusions: association of the APOE polymorphism with disability and lack of association with mortality support the view that APOE gene actions may be more significant as modulators of frailty than of longevity. [ABSTRACT FROM AUTHOR]