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Introduction: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty, and cognitive impairment. Methods: TTV viremia was measured in 1,131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7 ± 5.9 years), and then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail, and 141 nonfrail individuals (overall mean age: 77.5 ± 8.3 years). Results: TTV viremia ≥4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06–10.67, p < 0.0001) and cognitive impairment (OR: 3.49, 95% CI: 2.14–5.69, p < 0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000–1.773), only in the unadjusted model. No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. Conclusions: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study. Further research is necessary to clarify TTV's clinical relevance in the onset and progression of frailty and cognitive decline in older individuals. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of obesity increases with age and is higher in each younger generation (unfavorable generation shift). This may influence patterns of oxidative stress and inflammation. Age-related changes and generation shifts in markers of oxidative stress and inflammation were investigated, specifically addressing the role of body mass index (BMI).Methods: Four generations (aged 26-35, 36-45, 46-55, and 56-65 at baseline) (N = 5,155) were examined every 5 years for 15 years between 1993 and 2012. Random coefficient analyses were used to study age-related changes and generation shifts in BMI, γ-glutamyltransferase (GGT), uric acid (UA), and C-reactive protein (CRP).Results: Levels of BMI, UA, and CRP increased in all generations up to age 75, whereas GGT increased up to age 55. No consistent generation shifts were observed for GGT, UA, and CRP (P ≥ 0.05). Participants with a stable BMI (change ≤1 kg/m(2) /15 years) had either no or small increases with age in GGT, UA, and CRP, whereas participants with increasing BMI (increase >1 kg/m(2) /15 years) had much larger increases (P < 0.01).Conclusions: The unfavorable age-related changes in obesity-related biochemical markers, particularly among individuals with increasing BMI, show the importance of maintaining a healthy weight to improve population levels of oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Genome maintenance is considered a prime longevity assurance mechanism as apparent from many progeroid human syndromes that are caused by genome maintenance defects. The ERCC1 protein is involved in three genome maintenance systems: nucleotide excision repair , interstrand cross-link repair, and homologous recombination. Here we describe in-life and post-mortem observations for a hypomorphic Ercc1 variant, Ercc1-/Δ7, which is hemizygous for a single truncated Ercc1 allele, encoding a protein lacking the last seven amino acids. Ercc1 mice-/Δ7 were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively. Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1-/Δ7 mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters. Together they define a segmental progeroid phenotype of the Ercc1-/Δ7 mouse model. [ABSTRACT FROM AUTHOR]

Abstract: Genetic defects in nucleotide excision repair (NER) are associated with premature aging, including cancer, in both humans and mice. To investigate the possible role of increased somatic mutation accumulation in the accelerated appearance of symptoms of aging as a consequence of NER deficiency, we crossed four different mouse mutants, Xpa −/−, Ercc6(Csb)−/−, Ercc2(Xpd) m/m and Ercc1 −/m , with mice harboring lacZ-reporter genes to assess mutant frequencies and spectra in different organs during aging. The results indicate an accelerated accumulation of mutations in both liver and kidney of Xpa defective mice, which correlated with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum had undergone a shift, in both organs, to G:C→T:A transversions, a signature mutation of oxidative DNA damage. Ercc1 −/m mice, with their short lifespan of 6 months and severe symptoms of premature aging, especially in liver and kidney, displayed an even faster lacZ-mutant accumulation in liver. In this case, the excess mutations were mostly genome rearrangements. Csb −/− mice, with mild premature aging features and no reduction in lifespan, and Xpd m/m mice, exhibiting prominent premature aging features and about 20% reduction in lifespan, did not have elevated lacZ-mutant frequencies. It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation. [Copyright &y& Elsevier]

Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lac-Z mutational target genes, we found mutations to accumulate with age at an organ- and tissue-specific rate. Also the spectrum of age-accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. To directly address this question we demonstrate that it is now possible to analyze single cells, isolated from old and young tissues, for specific alterations in gene expression. [ABSTRACT FROM AUTHOR]

Increased genomic instability has been found associated with cancer and aging. The p53 tumor suppressor protein is a major determinant of genomic instability as a regulator of cell cycle control and apoptosis in response to DNA damage. To investigate the rate of age-related mutation accumulation in the absence of p53, we crossed Trp53 null mice with transgenic mice harboring a lacZ mutational target gene. In the hybrid animals, lacZ mutation frequencies at early age (i.e. at about 2 months) were found to be the same as in the control lacZ animals. However, up until about 6 months, when the Trp53-knockout mice usually die from cancer, mutations were found to accumulate with age in the spleen, and to a lesser extent in the liver, at a more rapid rate than in the control Trp53+/+ or Trp53+/−, lacZ hybrid mice. Treatment of 2–3-month-old Trp53−/−, lacZ hybrid mice with the powerful mutagen ethyl nitrosourea (ENU) resulted in a higher number of mutations induced in the liver but not in the spleen, as compared to the Trp53+/+, lacZ mice. These results suggest that p53 is not an important determinant of gene mutation induction, either spontaneously during development or after treatment with a mutagen. The accelerated age-related accumulation of mutations in normal spleen and liver could be explained by the defect in apoptosis, which would prevent severely damaged cells from being eliminated. [Copyright &y& Elsevier]