Maarten P. Rozing

Familial Longevity Is Associated with Decreased Thyroid Function

CONTEXT A relation between low thyroid activity and prolonged life span in humans has been observed. Several studies have demonstrated hereditary and genetic influences on thyroid function. OBJECTIVE The objective of the study was to test whether low thyroid activity associated with extreme longevity constitutes a heritable phenotype, which could contribute to the familial longevity observed in the Leiden Longevity Study. DESIGN This was a cross-sectional study. SETTING The study was conducted at a university hospital in the city of Leiden, The Netherlands. PARTICIPANTS Eight hundred fifty-nine nonagenarian siblings (median age 92.9 yr) from 421 long-lived families participated in the study. Families were recruited from the entire Dutch population if at least two long-lived siblings were alive and fulfilled the age criterion of age of 89 yr or older for males and 91 yr or older for females. There were no selection criteria on health or demographic characteristics. INTERVENTION Blood samples were taken for determination of serum parameters of thyroid function. MAIN OUTCOME MEASURE We calculated the family mortality history score of the parents of the nonagenarian siblings and related this to thyroid function parameters in the nonagenarian siblings. RESULTS We found that a lower family mortality history score (less mortality) of the parents of nonagenarian siblings was associated with higher serum TSH levels (P = 0.005) and lower free T(4) levels (P = 0.002) as well as lower free T(3) levels (P = 0.034) in the nonagenarian siblings. CONCLUSIONS Our findings support the previous observation that low thyroid activity in humans constitutes a heritable phenotype that contributes to exceptional familial longevity observed in the Leiden Longevity Study.

Familial longevity is marked by enhanced insulin sensitivity.

Insulin resistance is a risk factor for various age‐related diseases. In the Leiden Longevity study, we recruited long‐lived siblings and their offspring. Previously, we showed that, compared to controls, the offspring of long‐lived siblings had a better glucose tolerance. Here, we compared groups of offspring from long‐lived siblings and controls for the relation between insulin and glucose in nonfasted serum (n = 1848 subjects) and for quantitation of insulin action using a two‐step hyperinsulinemic‐euglycemic clamp (n = 24 subjects). Groups of offspring and controls were similar with regard to sex distribution, age, and body mass index. We observed a positive bi‐phasic linear relationship between ln (insulin) levels and nonfasted glucose with a steeper slope from 10.7 mU L−1 insulin onwards in controls compared to offspring (P = 0.02). During the clamp study, higher glucose infusion rate was required to maintain euglycemia during high‐dose insulin infusion (P = 0.036) in offspring, reflecting higher whole‐body insulin sensitivity. After adjustment for sex, age, and fat mass, the insulin‐mediated glucose disposal rate (GDR) was higher in offspring than controls (42.5 ± 2.7 vs. 33.2 ± 2.7 μmol kg−1 min−1, mean ± SE, P = 0.025). The insulin‐mediated suppression of endogenous glucose production and lipolysis did not differ between groups (all P > 0.05). Furthermore, GDR was significantly correlated with the mean age of death of the parents. In conclusion, offspring from long‐lived siblings are marked by enhanced peripheral glucose disposal. Future research will focus on identifying the underlying biomolecular mechanisms, with the aim to promote health in old age.

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study

OBJECTIVES: To explore measures of metabolic syndrome and glucose metabolism in families with exceptional longevity.

Genomics of human longevity

In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.

Low Serum Free Triiodothyronine Levels Mark Familial Longevity: The Leiden Longevity Study

BACKGROUND The hypothalamo-pituitary-thyroid axis has been widely implicated in modulating the aging process. Life extension effects associated with low thyroid hormone levels have been reported in multiple animal models. In human populations, an association was observed between low thyroid function and longevity at old age, but the beneficial effects of low thyroid hormone metabolism at middle age remain elusive. METHODS We have compared serum thyroid hormone function parameters in a group of middle-aged offspring of long-living nonagenarian siblings and a control group of their partners, all participants of the Leiden Longevity Study. RESULTS When compared with their partners, the group of offspring of nonagenarian siblings showed a trend toward higher serum thyrotropin levels (1.65 vs157 mU/L, p = .11) in conjunction with lower free thyroxine levels (15.0 vs 15.2 pmol/L, p = .045) and lower free triiodothyronine levels (4.08 vs 4.14 pmol/L, p = .024). CONCLUSIONS Compared with their partners, the group of offspring of nonagenarian siblings show a lower thyroidal sensitivity to thyrotropin. These findings suggest that the favorable role of low thyroid hormone metabolism on health and longevity in model organism is applicable to humans as well.

Thyroid Hormone Signaling and Homeostasis During Aging

Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.

Profit (p)-Index: The Degree to Which Authors Profit from Co-Authors

Current metrics for estimating a scientist’s academic performance treat the author’s publications as if these were solely attributable to the author. However, this approach ignores the substantive contributions of co-authors, leading to misjudgments about the individual’s own scientific merits and consequently to misallocation of funding resources and academic positions. This problem is becoming the more urgent in the biomedical field where the number of collaborations is growing rapidly, making it increasingly harder to support the best scientists. Therefore, here we introduce a simple harmonic weighing algorithm for correcting citations and citation-based metrics such as the h-index for co-authorships. This weighing algorithm can account for both the nvumber of co-authors and the sequence of authors on a paper. We then derive a measure called the ‘profit (p)-index’, which estimates the contribution of co-authors to the work of a given author. By using samples of researchers from a renowned Dutch University hospital, Spinoza Prize laureates (the most prestigious Dutch science award), and Nobel Prize laureates in Physiology or Medicine, we show that the contribution of co-authors to the work of a particular author is generally substantial (i.e., about 80%) and that researchers’ relative rankings change materially when adjusted for the contributions of co-authors. Interestingly, although the top University hospital researchers had the highest h-indices, this appeared to be due to their significantly higher p-indices. Importantly, the ranking completely reversed when using the profit adjusted h-indices, with the Nobel laureates having the highest, the Spinoza Prize laureates having an intermediate, and the top University hospital researchers having the lowest profit adjusted h-indices, respectively, suggesting that exceptional researchers are characterized by a relatively high degree of scientific independency/originality. The concepts and methods introduced here may thus provide a more fair impression of a scientist’s autonomous academic performance.

Serum triiodothyronine levels and inflammatory cytokine production capacity

Increasing evidence suggests that pro-inflammatory cytokines are at play in lowering peripheral thyroid hormone levels during critical illness. Conversely, thyroid hormones have been suggested to enhance production of inflammatory cytokines. In view of these considerations, we hypothesized a mutual association between triiodothyronine and pro-inflammatory cytokines. Therefore we evaluated the relation between both circulating and induced inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study. We found that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, higher serum free triiodothyronine levels were related to higher production capacity of pro-inflammatory cytokines after stimulation with lipopolysaccharide. By combining in vivo and ex vivo data, we were able to demonstrate for the first time the existence of a potential feedback mechanism between thyroid function and immune production capacity. We conclude that maintenance of normal thyroid function might be important for a preserved immune response in elderly human populations.

The maintenance gap: a new theoretical perspective on the evolution of aging

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, ‘maintenance requirement’ has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation. Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms. This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.

Senescence rates in patients with end‐stage renal disease: a critical appraisal of the Gompertz model

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end‐stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age‐specific mortality rates for European patients on dialysis (n = 274 221; follow‐up = 594 767 person‐years), for European patients with a functioning kidney transplant (n = 61 286; follow‐up = 345 024 person‐years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P < 0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.