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At least 19 recordsLinked to original sources
PubMed2026

Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.

About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.

Aging↗
PubMed1992

Excessive testicular progesterone secretion in aged male Fischer 344 rats: a potential cause of age-related gonadotropin suppression and confounding variable in aging studies.

Previous studies have inconsistently reported elevated sex steroid levels in aging male F344 rats, which frequently develop testicular Leydig cell tumors. The aims of this study were to characterize circulating steroid levels and to determine the in vivo source and functional significance of altered steroid secretion in these animals. Progesterone (P) and to a lesser extent estradiol (E2) levels were increased, while gonadotropins and testosterone (T) were decreased, in intact 24-mo-old compared to 12-mo-old rats. P levels were inversely correlated with gonadotropins and T. All old rats demonstrated Leydig cell hyperplasia or tumors. After orchidectomy, P levels were markedly decreased. Gonadotropin levels were similar in orchidectomized 24-mo compared to 3-mo-old rats. We conclude that the testis is the source of excessive P and E2 secretion in vivo in old F344 rats. Increased P (or E2) negative feedback may contribute to the suppression of gonadotropins and reproductive function in aging male F344 rats. Finally, excessive P secretion may be a confounding pathological variable in aging studies using this rat model.

17-alpha-Hydroxyprogesterone↗
PubMed1992

Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age.

OBJECTIVE: In women over the age of 45 years with continuing regular menstrual cycles, follicular phase FSH levels rise without an accompanying change in LH. We determined the effect of increasing age in women with regular cycles on the serum levels of FSH, LH, immunoreactive inhibin, progesterone and oestradiol. DESIGN: Single blood samples were taken during the early follicular phase (days 4-7) and again in the midluteal phase (3-12 days before the next menses) of the menstrual cycle. PATIENTS: Regularly cycling women aged 21-49 years participated in the study (and were grouped into four groups: 20-29, 30-39, 40-44 and 45-49 years in the follicular phase and three groups: 20-29, 30-39 and 40-49 years in the luteal phase. MEASUREMENTS: Serum levels of FSH, LH, oestradiol, progesterone and immunoreactive inhibin were measured from the blood samples obtained. RESULTS: Follicular phase Mean follicular phase levels of immunoreactive inhibin were significantly lower in the 45-49 year age group (P less than 0.05) than in the younger age groups (128 U/l in the 45-49 year age group vs 239, 235 and 207 U/l in the 20-29, 30-39, 40-44 year age groups respectively), while mean FSH levels were significantly higher in the 45-49 year age group (P less than 0.05, 13.0 IU/l in the 45-49, 4.9, 5.5 and 5.2 IU/l in the 20-29, 30-39 and 40-44 year age groups respectively). Mean oestradiol levels in the 45-49 year age group were significantly lower only when compared to age group 30-39 years (P less than 0.05, 130 vs 210 pmol/l). There was no significant difference in oestradiol levels between the 45-49 year age group and the 20-29 and 40-44 year age groups. LH levels did not differ significantly across age groups. There was also a significant negative correlation between serum immunoreactive inhibin and FSH (r = -0.45, P less than 0.05) and between oestradiol and FSH (r = -0.35, P less than 0.05). There was a significant negative relationship between immunoreactive inhibin and age (r = -0.46, P less than 0.05). For every 10-year increase in age, average immunoreactive inhibin decreased by an estimated 49.3 U/l. As age increased, average FSH levels exhibited a two-phase linear increase with the change-point estimated at 42.97 (1.42) (estimate (SE)) years. Prior to 42.97 years, FSH barely changed; after 42.97 years there was a significant (P less than 0.05) increase in FSH as age increased. Oestradiol levels did not change significantly until an estimated 37.9 years of age, but then decreased significantly (P less than 0.05) with increasing age. Luteal phase Levels of FSH, LH, serum immunoreactive inhibin, oestradiol and progesterone fell slowly with increasing age. There was a significant correlation between serum immunoreactive inhibin with progesterone (r = 0.41, P less than 0.05) but there was no correlation between serum immunoreactive inhibin LH or FSH. CONCLUSION: The results are consistent with a role for serum immunoreactive inhibin, in addition to oestradiol, in the regulation of FSH during the follicular phase of the menstrual cycle as a function of increasing age. This is postulated to reflect diminished folliculogenesis as age progresses with the known decline in the numbers of primordial follicles in the ovary as the menopause approaches.

Adult↗
PubMed1975

Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16 with allowance for midparent height.

Multiple regression equations for predicting the adult height of boys and girls from height and bone age at ages 4 and upwards are presented. There is a separate equation for each half year of chronological age; and for pre- and postmenarcheal girls at ages 11 to 14. These are based on longitudinal data from 116 boys and 95 girls of the Harpenden Growth Study and the London group of the International Children's Centre longitudinal study. The bone age used is the revised version of the Tanner-Whitehouse standards, omitting the score for carpal bones (RUS age, TW 2 system). Boys aged 4 to 12 are predicted in 95% of instances to within plus or minus 7 cm of true height, and at ages 13 and 14 to within plus or minus 6 cm. Girls ages 4 to 11 are predicted to within plus or minus 6 cm; premenarcheal girls aged 12 and 13 to within plus or minus 5 and plus or minus 4 cm, respectively; and postmenarcheal girls aged 12 and 13 to within plus or minus 4 and plus or minus 3 cm, respectively. Prediction can be somewhat imporved by allowing for midparent height. One-third of the amount that midparent height differs from mean midparent height is added or subtracted. An alternative system of equations which are based on initial classification by bone age rather than chronological age is given. These have about the same accuracy as the equations based on initial classification by chronological age, but allowance for bone age retardation is less. It is not clear which system is preferable. The equations probably apply to girls complaining of tall stature and boys or girls complaining of shortness and needing reassurance as to normality. In clearly pathological children, such as those with endocrinopathies, they do not apply.

Adolescent↗
PubMed1992

Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting.

It is well recognized that age at onset of Huntington disease (HD) is strongly influenced by the sex of the affected parent, and this has lead to suggestions that genetic imprinting or maternal specific factors may play a role in the expression of the disease. This study evaluated maternal and paternal ages, birth order, parental age at onset, and sex of the affected parent and grandparent in 1,764 patients in the National HD Roster by using linear-regression techniques which incorporated a weighted least-squares approach to accommodate the correlation among siblings. It was found that paternal age is negatively associated with age at onset of HD, particularly among subjects who inherit the mutant gene from grandfathers. Apparent associations between age at onset and birth order and between age at onset and maternal age were not significant after adjustment for paternal age. The paternal age effect is strongest among juvenile-onset cases and individuals with anticipation of greater than or equal to 10 years, although it is detectable across the entire age-at-onset distribution. The tendency for older fathers, including those not transmitting the HD gene, to have affected offspring with early-onset disease may be consistent with a gene imprinting mechanism involving DNA methylation. Because paternal age in unaffected fathers is also a significant determinant of age at onset, methylation in this context might involve HD modifier genes or the normal HD allele.

Adolescent↗
PubMed1978

Down syndrome, paternal age, maternal age and birth order.

Recent cytogenetic evidence has shown that trisomy 21 can arise, perphaps even in substantial proportion, from paternal nondisjunction. The statistical association between Down syndrome incidence and maternal age, paternal age and birth order has been studied in a sample of over 4000 cases. The size of this sample made it possible to control for the effect of maternal age by single years of age during the search for a paternal age effect and vice versa, and the importance of such stringent control is emphasized. The maternal age association was confirmed with an extremely high degree of statistical significance while no independent effect of paternal age was found; indeed, the rates at paternal ages over 45 years appear to be nearly constant. After adjusting for the effects of parental age, a significant inverse association of birth order with incidence was noted. It also appears that the incidence among very young mothers may be high: for maternal ages 15 years and less the rates seem to be equivalent to those found at 30 or 35 years. In order to help answer the question of whether the maternal age association is the result of increasing rates of nondisjunction or of some other mechanism (for example, an age related defect in a spontaneous abortion screening mechanism), the proportion of cases due to maternal and paternal nondisjunction at different parental ages must be determined.

Adolescent↗
PubMed1992

Age and gender effects on ondansetron pharmacokinetics: evaluation of healthy aged volunteers.

Modest differences in the clearance of the 5HT3 antagonist, ondansetron, among different age groups were detected in two groups of healthy elderly volunteers, one group aged 61 to 74 years ("elderly") and the other 75 to 82 ("aged") years, in addition to young healthy subjects. Both a single 0.15 mg/kg intravenous dose and a single 8 mg oral dose were administered according to a randomized crossover design with a minimum 3-day washout period between treatments. Mean plasma clearance decreased (young, 0.349 L/hr/kg; elderly, 0.279 L/hr/kg; aged, 0.214 L/hr/kg; p less than 0.05) with increasing age. Volume of distribution at steady state was unaffected by age (young, 1.81 L/kg; elderly, 1.94 L/kg; aged, 1.71 L/kg), resulting in increases in mean plasma half-life (young, 3.4 hours; elderly, 4.5 hours; aged, 5.4 hours) and mean absolute bioavailability (young, 57%; elderly, 61%; aged, 69%) with increasing age. Female subjects cleared ondansetron more slowly than males (p less than 0.05), resulting in higher absolute bioavailability. Ondansetron was well tolerated by all age groups with no increase in the number of adverse events observed in older volunteers.

Administration, Oral↗
PubMed2026

Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.

Aging is a primary risk factor for chronic diseases, yet its progression varies among individuals and between sexes. Here, under the X-Age Project, we profiled the clinical aging phenome of the Multicentric Chinese Aging Study (mCAS) through a cross-sectional analysis of 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers. These profiles enabled sex-specific clinical aging clocks that revealed divergent aging trajectories between women and men during midlife that converged in later life. Phenome-wide analyses revealed age-related accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, such as carcinoembryonic antigen and human epithelial protein 4. These age-accumulating factors induced senescence-related phenotypes in human endothelial cells. Furthermore, a high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging. Together, this work establishes metabolic and tumor marker accumulation as actionable drivers of human aging, paving the way for personalized, sex-stratified geroprotective interventions.

Humans↗
PubMed1976

A comparison of age estimation using discriminant function analysis with some other age estimations of unknown skulls.

Available methods of estimating the ages of unknown skulls are notoriously inaccurate. Making use of a unique opportunity to view several hundreds of remains from two nineteenth century cemeteries, various methods of estimating age were tested. A statistical method which gives relative weighting to each age indicator before reducing the data to a single pooled age estimate was found to be the most reliable. The greater the number of criteria which were utilized for age estimation, the more highly correlated was the estimated age of remains with the actual age at death. The degree of accuracy in estimating the ages of skulls of under 20 years was relatively high, when only the stage of development of dental tissues was examined. With increasing age over 20 the accuracy decreased, particularly at ages over 45. The range of age distribution of skulls estimated from published data on suture closure tended to be more restricted than that which may acutally occur.

Adult↗
PubMed1979

The effect of aging on the synthesis of hexosamine-containing substances from rat costal cartilage. A decrease in sulfation of chondroitin sulfate with aging.

The amount of glycosaminoglycan (GAG) in dry costal cartilage tissue of rats decreased with aging, while the GAG content in mg DNA (unit cartilage cell) remained the same with aging. These results can be explained by the finding that the total number of cartilage cells decreased with aging. Electrophoretic analysis showed that chondroitin 4-sulfate was the major GAG in rat costal cartilage of various ages. Rat costal cartilage of different ages was incubated with radioactive precursors, and newly synthesized GAG was prepared and the radioactivity analyzed to determine the biosynthetic activity. As to changes in the radioactivity uptake with aging per mg dry cartilage tissue, aging influenced [35S]sulfate incorporation into GAG more significantly than [3H]glucosamine incorporation into GAG. There was a significant decrease in the specific radioactivity of [35S]sulfate per mg DNA (unit cartilage cell), whereas the specific radioactivity of [3H]glucosamine per mg DNA did not change significantly with aging. Both the total sulfotransferase activity and the specific activity per mg DNA decreased significantly with aging. Analysis of disaccharide units formed after chondroitinase ABC digestion of labeled GAG isolated from young and old cartilage showed that the percentage of incorporation of [3H]glucosamine into deltaDi-OS increased significantly with aging. These results suggested that the appearance of nonsulfated positions in the structure of the chondroitin sulfate chain increased with aging. On the basis of gel chromatography on Bio-Gel A-1.5 m no significant difference in the approximate molecular size of chondroitin sulfate was observed between the young and old GAG samples. The present study indicated that the sulfation of chondroitin sulfate chains from rat costal cartilage decreased with the process of aging.

Aging↗
PubMed2026

Understanding and making sense of epigenetic age misalignment across different aging clocks.

The output of an epigenetic aging clock can vary depending on the training method utilized, cell type composition, the nature of the training dataset, the technology used to generate the methylomic data, acute stressors, and other factors. On an individual level, epigenetic age can fluctuate across different clocks purely due to differences in model training. Among aging clock researchers, it is well-known that the epigenetic age of a single sample can vary across different models. Based on our observations and conversations with longevity scientists and stakeholders, however, this fact is often unappreciated among non-aging clock experts. To help bring more awareness to this important topic, we highlight key literature and, as an illustrative example, use eight blood-trained clocks to show that epigenetic age is frequently misaligned in a publicly available whole blood dataset. Our simple analysis revealed that the average sample difference between the youngest and oldest predicted ages across these clocks was 17 years. The smallest and largest individual-level differences observed were 4 and 45 years, respectively. Clock misalignment has implications for choosing which clock to utilize, interpreting the impact of an intervention on epigenetic age, personalized tracking, and relating epigenetic age to the abstract concept of biological age.

Humans↗
PubMed1992

The influence of increased age and age matching on graft survival after first cadaveric renal transplantation.

We examined the influence of donor and recipient age as well as close donor and recipient age matching by analysis of the actuarial survival of 397 consecutive first cadaveric renal transplants carried out in the years 1987 to 1990. Graft failure was defined as return to dialysis, transplant nephrectomy, or death of the recipient from any cause. Overall 1-, 2-, and 3-year actuarial graft survival was 87, 84, and 79%. No effect on graft survival in adult patients was seen of advanced age of either donor or recipient. The source of the donor whether from within or outside the North Western Regional Health Authority did not influence outcome whatever the donor age. Results from patients in whom the donor was within 5 years of the recipient's age were no different from those obtained when the age difference was greater than 5 years. These data do not support the hypothesis that close age matching influences graft survival. Age matching need not be used as a recipient selection criterion. As neither recipient nor donor age influenced early graft survival, consideration should be given to increasing the average age of both donors and recipients.

Adolescent↗
PubMed1978

Influence of mouse age and erythrocyte age on glutathione metabolism.

In order to determine whether the biological age of a mouse influences erythrocyte metabolism and erythrocyte aging in vivo, blood samples were collected from male C57/BL6J mice of different biological ages ranging from mature (10 months) to "very old" (37 months). In the very old mouse, compared with the mature mouse, the erythrocyte survival time was decreased, erythrocyte densities were increased, the concentrations of total free thiol and reduced glutathione, and glutathione reductase activity were decreased. Erythrocytes were separated into different density (age) groups by phthalate ester two-phase centrifugation or by albumin density-gradient centrifugation. The density-age relationship of erythrocytes was established by pulse-labelling with 59Fe in vivo and by subsequent determinations of specific radioactivity of erythrocyte fractions of different densities prepared during a chase period of 60 days. The age of erythrocytes in mice of all ages was directly related to density. Also, in older erythrocytes compared with younger erythrocytes, decreased concentrations of total free thiol and reduced glutathione, and decreased glutathione reductase activity were observed. These were the lowest in the old erythrocytes of very old mice. These results in aging erythrocytes from aging mice suggest that the glutathione status the erythrocyte may be an index of aging, not only of the cell but also of the organism.

Aging↗