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PubMed2000

Developmental progression of clock face drawing in children.

The clock drawing test has been routinely administered by many neuropsychologists as part of their testing battery with the adult population. Our study investigated the development of clock face drawing in normal children ages 6 to 12 years. Conceptualization of time and construction of the clock face were assessed by an adapted scoring system developed as part of the investigation. As a group, the results indicated an upward progression with regard to the concept of time through age 8 and clock construction through age 12. Results further demonstrated that number reversals were more frequent among left-handers but were no longer evident by age 7 regardless of handedness. It also was determined that left visuospatial neglect specific to the upper quadrant was relatively common in 6- and 7-year olds but not evidenced by age 8. Given the pattern of the findings, it is likely that the neglect was secondary to poor planning and not a visuo-spatial deficit. In general, development of clock face drawing most closely paralleled that of frontal lobe maturation. Implications of these findings and the usefulness of clock face drawing with the pediatric population are presented.

Age Factors↗
PubMed2026

Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

Humans↗
PubMed2001

Reproductive aging and mating: the ticking of the biological clock in female cockroaches.

Females are expected to have different mating preferences because of the variation in costs and benefits of mate choice both between females and within individual females over a lifetime. Workers have begun to look for, and find, the expected variation among females in expressed mating preferences. However, variation within females caused by changes in intrinsic influences has not been examined in detail. Here we show that reproductive aging caused by delayed mating resulted in reduced choosiness by female Nauphoeta cinerea, a cockroach that has reproductive cycles and gives live birth. Male willingness to mate was unaffected by variation in female age. Females who were beyond the optimal mating age, 6 days postadult molt, required considerably less courtship than their younger counterparts. Females who were older when they mated had fewer offspring per clutch and fewer clutches than females who mated young. Thus, reduced choosiness was correlated with a permanent reduction in fertility. There was no difference in overall senescence among females, and thus the reduction in clutch size did not result in the expected increased lifespan. We suggest that reproductive aging in N. cinerea, similar to aging in general, occurs because the maintenance of oocytes is costly, and selection is relaxed after the optimal mating period. Our results further suggest that selection for continued choosiness is also relaxed and supports direct selection on female choosiness and a cost to choosiness.

Aging↗
PubMed2006

"Diabetes of the elderly" and type 2 diabetes in younger patients: possible role of the biological clock.

The increased prevalence of type 2 diabetes in the aged has been recognized for a long time. Within the last decades, a growing number of younger subjects and even children are prone to develop type 2 diabetes. In both groups, aged and young, the biological clock, located in the suprachiasmatic nucleus of the hypothalamus (SCN) is malfunctioning as evidenced by disturbed sleep cycles and altered circadian rhythms. While elderly patients have an impaired function of the SCN due to the degeneration of neurons, we propose that in younger subjects the clock loses its "feeling" for internal and external rhythms caused by the modern lifestyle. Sleeping late and less coupled with constant metabolic excess alter both internal and external environmental stimuli to the brain. In response to these alterations, the rhythm of the biological clock is disrupted which may lead to the metabolic syndrome and type 2 diabetes.

Adult↗
PubMed2004

Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice.

The amplitudes of many circadian rhythms, at the behavioral, physiological, cellular, and biochemical levels, decrease with advanced age. Previous studies suggest that the amplitude of the central circadian pacemaker is decreased in old animals. Recently, it has been reported that expression of several circadian clock genes, including Clock, is lower in the master circadian pacemaker of old rodents. To test the hypothesis that decreased activity of a circadian clock gene renders animals more susceptible to the effects of aging, we analyzed the circadian rhythm of locomotor activity in young and old wild-type and heterozygous Clock mutant mice. We found that the effects of age and the Clock mutation were additive. These results indicate that age-related changes in circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants, suggesting that the Clock mutation does not render mice more susceptible to the effects of age on the circadian pacemaker.

Aging↗
PubMed2000

Biologic activity of mitochondrial metabolites on aging and age-related hearing loss.

HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND: Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS: Twenty-one Fischer rats, aged 24 months, were divided into three groups: acetyl-l-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS: The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS: These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities.

Acetylcarnitine↗
PubMed2004

Scoring clock tests for dementia screening: a comparison of two scoring methods.

OBJECTIVE: To compare the dementia screening performance of two scoring systems of the clock drawing test. METHODS: A sample of 1199 elderly subjects was administered the clock drawing test as part of a study on aging and dementia. The clock drawings were scored using published criteria for the two scoring systems that were compared. Additionally, a selection of 103 drawings was scored by three different raters to evaluate inter-rater agreement within each of the two methods. For a selection of 473 drawings the final diagnosis on the presence or absence of dementia was known. For these drawings accuracy for the detection of dementia was compared between the two methods. RESULTS: The four-item scoring system (Kappa 0.76; sensitivity 0.97; specificity 0.32; PPV 0.53; NPV 0.93) was found to be a little more reliable and as accurate as the six-item scoring system (Kappa 0.67; sensitivity 0.96; specificity 0.42; PPV 0.56; NPV 0.94). CONCLUSION: Since both scoring systems showed largely similar results, primary care physicians and other health care providers should be encouraged to use the four-item scoring checklist as it is easier and requires less time than the more elaborate checklist of the six-item system.

Aged↗
PubMed1985

Environmental and genetic factors that influence immunity and longevity in mice.

Many different theoretical approaches may be taken toward understanding the association between aging and immunologic malfunction. The leading theory is based on the natural phenomenon of thymic involution and argues that the T-dependent lymphoid system is genetically programmed to decline in effectiveness, possibly through altered endocrine and central nervous system controls. The "thymic time clock" theory of aging is strongly supported by the consistent finding of defective cellular immunity functions in aged humans and animals and an associated development of the age-related diseases. In several animal models, including autoimmune-prone strains, high spontaneous tumor incidence strains, and normal long-lived strains, it has been possible to forestall the development of the major diseases of aging and extend longevity by restricting diet. The predominant effect of dietary restriction is prolongation of immunologic vigor and retardation of the immunologic dysfunction that normally occurs with age. Studies on environmental factors affecting longevity such as these and others which demonstrate a complex interaction between genes influencing longevity underscore the complexity and challenge of aging research.

Aging↗
PubMed2026

Epigenetic age acceleration is not strongly associated with cardiorespiratory fitness in heart failure: a pilot study.

BACKGROUND: In heart failure (HF), standard measures such as left ventricular ejection fraction and cardiopulmonary exercise testing incompletely capture interindividual differences in disease status or prognosis. DNA methylation (DNAm) epigenetic clocks, which estimate biological age and epigenetic age acceleration (EAA), may provide complementary insight into cardiorespiratory fitness and systemic aging in HF. RESEARCH DESIGN AND METHODS: We analyzed peripheral blood DNAm from fourteen patients enrolled in REDHART2, a clinical trial of interleukin-1 blockade following hospitalization for acute systolic HF. Genome-wide DNAm was assayed using Illumina EPIC arrays and several clocks were applied to these data. Associations between biological age or EAA and cardiorespiratory fitness measures, inflammatory markers, and clinical parameters were evaluated. RESULTS: All epigenetic clocks demonstrated moderate to strong correlations with chronological age. Biological age was consistently associated with measures of cardiorespiratory fitness, particularly oxygen consumption normalized to fat free mass (VO2_FFM). However, chronological age showed similar associations, and biological age did not significantly improve prediction of VO2 parameters beyond chronological age alone. EAA was not significantly associated with cardiorespiratory fitness for any clock. CONCLUSIONS: In this pilot study, neither biological age nor EAA provided significant predictive value beyond chronological age for cardiorespiratory fitness in patients with HF. CLINICAL TRIAL REGISTRATION NUMBER: NCT03797001.

DNA methylation↗
PubMed1979

Molecular clocks, molecular profiles, and optimum diets: three approaches to the problem of aging.

It has been hypothesized that the deamidation of glutaminyl and asparaginyl residues serves as a molecular clock for many biological processes including protein turnover, development, and aging. At present, this hypothesis has passed some experimental tests which are necessary but not sufficient for its acceptance. The current state of evidence about deamidation as a molecular clock is discussed. In addition, since the molecular biology of aging, especially in humans, is only partly understood, it is of value to develop quantitative, empirical measures of physiological human age and to use these measures to evaluate alternative human living conditions, especially easily adopted alternatives like variations in diet. This may allow some decrease in the suffering and loss from human aging until such time as molecular biology provides superior and more intellectually satisfying answers. An empirical system which consists of quantitative measurement of several hundred human chemical constituents followed by computerized pattern recognition is described. It is hoped that this system will eventually become an aid in the minimization of the rate of human aging through changes in diet and other factors.

Adult↗
PubMed1983

Chronobiology at the cellular and molecular levels: models and mechanisms for circadian timekeeping.

This review considers cellular chronobiology and examines, at least in a superficial way, several classes of models and mechanisms that have been proposed for circadian rhythmicity and some of the experimental approaches that have appeared to be most productive. After a brief discussion of temporal organization and the metabolic, epigenetic, and circadian time domains, the general properties of circadian rhythms are enumerated. A survey of independent oscillations in isolated organs, tissues, and cells is followed by a review of selected circadian rhythms in eukaryotic microorganisms, with particular emphasis placed on the rhythm of cell division in the algal flagellate Euglena as a model system illustrating temporal differentiation. In the ensuing section, experimental approaches to circadian clock mechanisms are considered. The dissection of the clock by the use of chemical inhibitors is illustrated for the rhythm of bioluminescence in the marine dinoflagellate Gonyaulax and for the rhythm of photosynthetic capacity in the unicellular green alga Acetabularia. Alternatively, genetic analysis of circadian oscillators is considered in the green alga Chlamydomonas and in the bread mold Neurospora, both of which have yielded clock mutants and mutants having biochemical lesions that exhibit altered clock properties. On the basis of the evidence generated by these experimental approaches, several classes of biochemical and molecular models for circadian clocks have been proposed. These include strictly molecular models, feedback loop (network) models, transcriptional (tape-reading) models, and membrane models; some of their key elements and predictions are discussed. Finally, a number of general unsolved problems at the cellular level are briefly mentioned: cell cycle interfaces, the evolution of circadian rhythmicity, the possibility of multiple cellular oscillators, chronopharmacology and chronotherapy, and cell-cycle clocks in development and aging.

Acetabularia↗
PubMedDate not supplied

Visuospatial functioning and spatial orientation in a community-based sample of healthy very old persons.

A population-based sample (n=219) of healthy older adults ranging from 75 to 96 years of age was examined in tests measuring visuospatial ability (modified Block Design Test) and spatial orientation (Clock Setting Test and Clock Reading Test). Results indicated an age-related deterioration in both visuospatial abilities and spatial orientation. Block Design performance was higher under self-paced than under paced conditions across the entire age range, although the beneficial effects from decreased pacing tended to increase with increasing age. Also, the clock test data suggest that the abilities underlying time recognition (clock reading) may deteriorate later in the normal aging process than those underlying time drawing (clock setting). Finally, regression analyses on the relationship between a variety of demographic, psychometric, and biological variables and visuospatial functioning showed that, in order of importance, years of age, Mini Mental State Examination (MMSE), and education, were significantly related to task performance.

Journal Article↗
PubMed1996

Invertebrate gerontology: the age mutations of Caenorhabditis elegans.

Ageing is a complex phenomenon which remains a major challenge to modern biology. Although the evolutionary biology of ageing is well understood, the mechanisms that limit lifespan are unknown. The isolation and analysis of single-gene mutations which extend lifespan (Age mutations) is likely to reveal processes which influence ageing. Caenorhabditis elegans is the only metazoan in which Age mutations have been identified. The Age mutations not only prolong life, but also confer a complex array of other phenotypes. Some of these phenotypes provide clues to the evolutionary origins of these genes while others allude to mechanisms of lifespan-extension. Many of the Age genes interact and share a second common phenotype, that of stress resistance. Rather than invertebrate ageing being determined by a 'clock mechanism', a picture is emerging of ageing as a non-adaptive process determined, in part, by resistance to intrinsic stress mediated by stress-response genes.

Aging↗
PubMed1996

Foot-ankle injuries: influence of crash location, seating position and age.

Foot-ankle injuries have increased in relative importance in recent years. As a basis for future countermeasures, an epidemiology study has been undertaken using Swedish accident data from Folksam Insurance. The database consists of 805 foot-ankle injuries out of 57,949 car occupant injuries reported from 1985 to 1991. The influence of crash location, seating position and occupant age is determined for the frequency, incidence and rate of foot-ankle injury in car crashes. Frontal car crashes produce 76% of the AIS 2-3 foot-ankle injuries with 13% in side impacts and 8% in roll-overs. The rate of AIS 2-3 foot-ankle injury is 24.7 per 1000 occupants injured in all crash locations and is similar irrespective of seating positions. Ankle fractures and sprains both occur at an incidence of 3.7 per 1000 injuries, followed by malleolus fractures at 2.7 and midtarsal fractures at 2.4. The foot-ankle injury incidence and rate are significantly greater (p < 0.01) in near oblique-frontal crashes than for 12 o'clock frontals. For drivers in 11 o'clock and front passengers in 12 o'clock, the incidence is 27.8 per 1000 injuries as compared to 17.5 for drivers and front passengers in 12 o'clock crashes. Occupant age is not as significant as seating position and crash location; however, there are higher incidences for rear occupants > or = 60 years old in oblique frontal crashes. Using the new AAAM Impairment Injury Scale (IIS), 48% of the foot-ankle injuries are rated with residual impairment IIS 1-2. The incidence in near-seated occupants is 1.5 times greater in oblique frontal crashes than in frontals. The incidence for IIS 1-2 impairment in near oblique-frontal crashes is 12.8 per 1000 occupant injuries as compared to 8.3 in frontal crashes.

Abbreviated Injury Scale↗
PubMed1999

Emerging and entraining patterns of the sleep-wake rhythm in preterm and term infants.

It has been repeatedly reported that the sleep-wake rhythm in infants entrains around 3-4 months of age after a transient free-run rhythm. To clarify the emerging and entraining patterns of the sleep-wake rhythm, the sleep and wakefulness of 84 infants (44 preterm and 40 term infants) were longitudinally recorded at home for more than 16 weeks by the day-by-day plot method. Our results showed that the entrained sleep-wake rhythm emerged after transient manifestation of either ultradian or irregular sleep-wake patterns for 3-4 weeks in 75% of the infants. Only 7% of the infants showed a free-running sleep-wake rhythm before the entrainment. These facts suggest that most infants would be entrained to an ordinary daily schedule of mothers without expression of overt free-running rhythm of the biological clock. The mean age of the entrainment was 44.8 postconceptional weeks. There were no significant differences in either frequency of each pattern or the mean age of the entrainment, between preterm and term infants. In conclusion, the entrained sleep-wake rhythm emerges around 1 corrected month, after ultradian patterns in the majority of infants.

Circadian Rhythm↗