D. van Heemst

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.

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.

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.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Proton magnetic resonance spectroscopy shows lower intramyocellular lipid accumulation in middle-aged subjects predisposed to familial longevity.

Families predisposed to longevity show enhanced glucose tolerance and skeletal muscle insulin sensitivity compared with controls, independent of body composition and physical activity. Intramyocellular lipid (IMCL) accumulation in skeletal muscle has been associated with insulin resistance. Here, we assessed whether subjects enriched for familial longevity have lower IMCL levels. We determined IMCL levels in 48 subjects from the Leiden Longevity Study, comprising 24 offspring of nonagenarian siblings and 24 partners thereof as control subjects. IMCL levels were assessed noninvasively using short echo time proton magnetic resonance spectroscopy ((1)H-MRS) of the tibialis anterior muscle with a 7 Tesla human MR scanner. IMCL levels were calculated relative to the total creatine (tCr) CH3 signal. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). After correction for age, sex, BMI, and physical activity, offspring of long-lived nonagenarian siblings tended to show lower IMCL levels compared with controls (IMCL/tCr: 3.1 ± 0.5 vs. 4.5 ± 0.5, respectively, P = 0.051). In a pairwise comparison, this difference reached statistical significance (P = 0.038). We conclude that offspring of nonagenarian siblings predisposed to longevity show lower IMCL levels compared with environmentally matched control subjects. Future research should focus on assessing what mechanisms may explain the lower IMCL levels in familial longevity.

Lifestyle and youthful looks

Lifestyle has been proven to have a dramatic effect on the risk of age‐related diseases. The association of lifestyle and facial ageing has been less well studied.

Plasma levels of apolipoprotein E and cognitive function in old age.

Abstract:  The relationship between structural variants of the apolipoprotein E gene, APOEɛ2/ɛ3/ɛ4, and dementia is well established, whereas the relationship of plasma apoE levels with dementia is less clear. Plasma apoE levels are under tight genetic control but vary widely within the various genotypes indicating that the APOEɛ2/ɛ3/ɛ4 locus explains only a small fraction of this variation. Here we studied the association of plasma apolipoprotein E (apoE) levels with cognitive function in the elderly population at large. Within the Leiden 85‐plus Study, a prospective population‐based study of subjects aged 85 years, we measured plasma apoE level and genotype at base line. During a 5‐year follow‐up period, cognitive function was annually assessed using the Mini Mental State Examination (MMSE) and a standardized neuropsychological test battery. Among ɛ3ɛ3 carriers (n= 324), high plasma apoE levels associated with impaired global cognitive function (–1.10 points change in MMSE score per one standard deviation increase of plasma apoE level, P= 0.001), as well as lower attention (P= 0.064), speed and memory function (all P < 0.05). Adjustment for cardiovascular risk factors and exclusion of all subjects who suffered a stroke did not materially change the associations. Similar estimates were obtained in ɛ3ɛ4 carriers (n= 100), but not in ɛ2ɛ3 carriers (n= 90). We conclude that in old age, in non‐ɛ2‐allele carriers, high plasma apoE levels are associated with cognitive impairments, independent of genotype, cardiovascular risk factors, and stroke.

Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study

Background  Insulin‐like growth factor (IGF)‐1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression.

A simple and versatile method for frequent 24 h blood sample collection in healthy older adults

Graphical abstract

Markers of health and disease and pigmented spots in a middle‐aged population

DEAR EDITOR, Pigmented cutaneous spots, such as actinic/solar lentigines, develop with advancing age and are most commonly observed in chronically sun-exposed areas of the skin, such as the face, neck and dorsa of the hands. Actinic lentigines are characterized histopathologically by hyperpigmentation of the epidermal basal layer with an elongation of the epidermal rete ridges, and an increase in the number of dermal melanophages with deficient migration and digestive abilities. Other than cumulative ultraviolet (UV) exposure, risk factors for actinic lentigines are largely unknown. However, endocrine abnormalities, genetic factors, oestrogen levels, thyroid dysfunction and lower vitamin D levels have been identified as potential risk factors for some disorders of pigmentation (e.g. acanthosis nigricans, melasma and vitiligo). Thus there may be intrinsic factors that influence the development of common but benign pigmented spots such as actinic lentigines. In the present study, our purpose was to investigate the association between independent markers of health and disease and the extent of pigmented spots in a middle-aged Dutch white population. The research question was addressed using a cross-sectional study design embedded in a random subpopulation of the Leiden Longevity Study, with data available on markers of health and disease and on pigmented spots. For the analyses, participants were ranked into tertiles based on the measures investigated. The extent and severity of pigmented spots present were determined through grading of facial photographs by two expert dermatologists (T.W.G. and S.O.). A detailed description of the study design, recruitment, data collected and statistical analyses are reported in Appendix S1 (see Supporting Information). The study population (n = 623) had a mean age of 63 0 6 7 years, with 53 6% women (more characteristics are presented in Table S1; see Supporting Information). In statistical models comprising each determinant separately, a higher age and female sex, and (after adjusting for age and