Decline in insulin action is a metabolic feature of aging and may be involved in the development of age related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer’s disease (AD). We have previously showed that IGF-1 infused intra-cerebro-ventricularly (ICV) enhances hepatic insulin sensitivity on suppression of glucose output. In contrast ICV infusion of IGF-1 binding protein -3 (IGFBP3) causes insulin resistance in the periphery, independent of its binding to IGF-1. A novel mitochondrial peptide, Humanin (HN), has been recently recognized for its neuro-protective role against AD-related neurotoxicity. We have cloned it as an IGFBP3 partner. Here we show that, in addition to its neuro-survival effects, HN regulates both hepatic and peripheral insulin action via the hypothalamus. Infusion of HN ICV significantly improves overall insulin sensitivity, both at the liver and skeletal muscle. The central effects of HN on insulin action are associated with activation of hypothalamic STAT-3 signaling; effects that are negated by co-inhibition of hypothalamic STAT-3. Furthermore, endogenous IGFBP-3 in the hypothalamus tempers the effects of HN on glucose metabolism. The significantly higher insulin-sensitizing effects of HN analogues that do not bind IGFBP-3 demonstrate this. Peripheral infusions of novel HN derivatives reproduce the insulin-sensitizing effects of central HN. HN represents a novel link between diabetes and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM. Importantly, acute regulation of peripheral insulin action is probably elicited in the hypothalamus and the integrity of GH/IGF system is probably needed to ensure m normal metabolism with aging.
Telomeres protect and stabilize chromosome ends. Telomere "caps” consist of simple DNA sequences bound to protein factors. Telomerase is a specialized ribonucleprotein enzyme that replenishes the DNA at telomeres, through its unique mechanism of internal RNA-templated addition of telomeric DNA, and also protects the telomeres, thus counteracting cell senescence. Without telomeric DNA and its special way of replicating, human chromosome ends dwindle down, eventually causing cells to stop dividing. Such loss of telomere function and consequent cellular senescence may occur in human aging.
In human adults, telomerase is active in a great many more normal cell types than previously thought. Evidence is emerging that the quantity of telomerase is limiting for tissue replenishment throughout human life and can be altered by non-genetic factors. In collaborative cross-sectional and longitudinal human studies (Epel et al, 2004; 2006; unpublished work), we have found that chronic psychological stress further lowers telomerase activity in unstimulated normal white blood cells of the body. Furthermore, low white blood cell telomerase was associated with six of the known major risk factors – including chronic psychological stress – for cardiovascular disease. This work adds to the growing evidence implicating normal-cell telomere maintenance in protection from common diseases of human aging.
Endocrine mutant mice have proven invaluable toward the quest to uncover mechanisms underlying longevity. Growth hormone (GH) and insulin like-growth factor (IGF) have been shown to be key players in physiological systems that contribute to aging processes including glucose metabolism, body composition and cellular protection. Examination of these mutant mice across several laboratories has revealed that differences exist in both the direction and magnitude of change, differences that may result in variation in life span. Growth hormone receptor knock out mice lack a functional GH receptor, therefore GH signaling is absent. These mice have been shown to lack the heightened oxidative defense mechanisms observed in other GH mutants yet live significantly longer than wild type mice. In this study, glutathione (GSH) and methionine (MET) metabolism was examined to determine the extent of variation in this mutant in comparison to the Ames dwarf, a mouse that exhibits delayed aging and life span extension of nearly 70%. Components of GSH and MET were altered in GHR KO compared to wild type controls. The results of these experiments suggest that these pathways may be partially responsible for differences observed in stress resistance and the capacity to respond to stressors, that in the long term, affect health and life span.
Energy balance in mammals is modulated by peripheral signals that inform the brain about the magnitude of fat stores, the amount of food in the gastrointestinal tract, and the level of nutrients such as glucose in the circulation. Among these, insulin and leptin are considered adiposity signals involved in the long-term maintenance of fat stores. Here we review the mechanisms of action of leptin and insulin in the hypothalamus and how these mechanisms are altered during aging in rat models. Aged rats are characterized by increased fat mass, central leptin and insulin resistance, and hyperleptinemia. Leptin resistance is manifested by its failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose tissue, and increase energy expenditure. Moreover, leptin and insulin signalling are decreased in hypothalamus from aged rats. Calorie restriction and fasting studies provide controversial data on the cause-effect interrelationship between increased adiposity and development of central leptin resistance. Although in the absence of obesity leptin resistance seems to be a characteristic of aged animals, adiposity could either reinforce it or cause an early onset of this resistance. More studies are necessary to clarify the role of hypothalamus in the development of age-associated obesity and insulin resistance.
Pit1 null (Snell dwarf) mice are long-lived mouse models that are resistant to cancer. Endogenous glucose production is lower in Snell dwarf than control mice during fasting. Does the reduction of glucose production provide resistance to cancer in Snell dwarf mice? First, we examined whether endogenous glucose production is also lower in Snell dwarf mice during feeding. The reduction of endogenous glucose production during feeding and fasting could reduce glucose utilization by cancer cells and provide resistance to cancer. Inhibition of endogenous glucose production by injection of glucose was enhanced in 13 month old female Snell dwarf mice. Second, we compared the incidence of cancer at time of death in old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for Snell dwarf and control mice in this study were 33 and 26 months, respectively. Elevated circulating adiponectin, a hormone produced by adipose tissue, was observed in 13 month old female Snell dwarf mice Snell dwarf mice. The elevation of adiponectin may provide Snell dwarf mice with resistance to cancer by inhibiting endogenous glucose production. Like Snell dwarf mice, Proph1 null (Ames dwarf) mice are long-lived mouse models that lack of GH, PRL and TSH and show reduced IGF-I and elevated adiponectin. However, in contrast to Snell dwarf mice, old Ames dwarf mice show a high incidence of cancer at the time of death similar to control mice. Hence, endocrine factors other than elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH provide old Snell dwarf mice with cancer resistance. Proteomics analysis of pituitary secretions revealed the lack of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II in Snell dwarfs. We confirmed the elevation of circulating Chromogranin B and Secretogranin II in Snell dwarf mice by radioimmunoassay. In summary, these results suggest that the pituitary gland and adipose tissue are part of a complex neuroendocrine system that inhibits endogenous glucose production and thereby reduces the risk of cancer.
Neuroactive steroids are secretory products of peripheral endocrine glands that modulate a variety of brain functions. A close relationship between neuroactive steroid structure and function becomes most evident under pathological circumstances. On one side, overproduction of glucocorticoid and mineralocorticoid neuroactive steroids may be detrimental to the hippocampus, which is enriched in glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Thus, a dysfunction of the adrenocortical system in aging and age-associated diseases (diabetes, hypertension), is able to cause hippocampal damage. Whereas aging and uncontrolled diabetes show a predominant GR overdrive, a MR overdrive characterizes hypertensive animals. Some abnormalities commonly found in the hippocampus of aging, diabetic and hypertensive animals include decreased neurogenesis, astrogliosis and neuronal loss in the hilus of the dentate gyrus (DG). On the other side, and in contrast to adrenal gland-derived steroids, estrogens qualify as hippocampal neuroprotectants. Given to middle age mice, estrogens stimulated proliferation and differentiation of newborn cells in the DG, decreased astrogliosis and increased hilar neuronal number. Similar estrogen effects were obtained in mice with streptozotocin-induced diabetes and in spontaneously hypertensive rats (SHR). The results suggest that in aging and age-associated diseases, adrenocortical steroid overdrive sensitizes the hippocampus to the pathological milieu imposed by a preexisting degeneration or illness. In this setting, estradiol neuroprotection rescues hippocampal parameters previously altered by the pathological environment.
The number of centenarians (and also of supercentenarians, older than 110 y.) is rapidly increasing through the world; at the end of 2006 they were 11.000 in Italy.
The definition of “autonomous centenarians” has been proposed to indicate centenarian subjects who exhibit a certain number of physiological functions within the normal limits, or in any case have better healthy conditions than relatively younger people, and therefore may be considered as example of “successful” aging. This definition seems to be preferable to the other of “healthy centenarians”, since the frequent occurrence in extreme longevity of pathologic conditions and of sensory disturbances may interfere with the correct evaluation of health and especially of the cognitive performances.
The study of neuroendocrine functions in long living subjects, such as centenarians without clinically relevant diseases, seems to be particularly interesting, in order to evaluate the biological features strictly related to the aging process and to distinguish them from the changes related to comorbidity and comedication, so frequently occurring in elderly people.
We recently studied 59 centenarians living in Pavia (North Italy), 7 men and 52 women, aged 100-107 years (mean age 101,8±4 SD), compared with 24 healthy old subjects (mean age 84,7±1.3) and 20 young controls (mean age 27,8±0.6). Our centenarians lived at home or in nursing homes; they were free from significant pathological conditions, but frequently had sensory disturbances affecting sight and hearing.
For the study of the neuroendocrine features of centenarians we especially focused on hormonal functions particularly involved in the control of the homeostasis and of the plasticity of the organism towards changes of the internal and external milieu as well as to stressful conditions, and hence particularly relevant for the maintenance of conditions of well being. Indeed we studied the secretory patterns of melatonin, cortisol and DHEAS, and of the TSH-thyroid axis.
The study of the circadian organization of melatonin secretion, due to ethical and technical limitations, was carried out by the evaluation of urinary 6-hydroxymelatonin sulphate (aMT6s), the main melatonin metabolite, whose excretion in the 24-hour cycle is parallel to the plasma hormonal levels. In particular, we measured AMT6s in two different 12 hours urine samples collected between 08.00 and 20.00 (daytime) and from 20.00 to 08.00 (nighttime).
The age-related impairment of melatonin secretion was clearly demonstrated by the evaluation of AMT6s urinary excretion in elderly subjects and in centenarians, when compared to young controls. Therefore, the weakening of melatonin signal persists also in extreme senescence.
When expressing both the diurnal and nocturnal AMT6s excretion as percent of the total 24 hours amount, also after correction for urinary volumes and creatinine clearance, the nocturnal rate was significantly higher than the diurnal one in centenarians as well as in young subjects, while no differences between day and night levels were found in old controls. These findings suggest a better maintenance of the physiological circadian organization of melatonin secretion in centenarians, by comparison with elderly people.
Since the melatonin circadian rhythm plays a role of endogenous synchronizer for different bioperiodic function, the persistence of such chronobiological parameter in extreme longevity could be of great interest for successfull aging.
The HPA axis was evaluated through the measure of the 24 hours urinary free cortisol excretion and the assay of cortisol and DHEA-s in a morning blood sample collected after an overnight fast, in order to evaluate the ratio between the two steroids, considered as a marker of the CNS steroidal milieu.
A statistically significant age-related impairment of urinary free cortisol excretion was evident also in centenarians; likewise,the age-related decline of DHEA-s levels persisted also in this group. However, the presence also in centenarians of reduced blood DHEA-s concentrations with the relative constancy of cortisol levels (expression of the adrenocortical biosynthetic dissociation linked to age itself) seems not to represent a negative factor for successful aging. Indeed the cortisol/DHEA-s molar ratio, whose increase expresses a neurotoxic steroidal milieu in the CNS, was significantly higher in elderly people than in young controls, but did not exhibit a further increase in centenarians. This finding might suggest a relative stop of the neurotoxic steroidal pattern after the threshold of one hundred years.
The study of the pituitary-thyroid axis was carried out by the measure of serum TSH, FT4,FT3 and rT3, and the evaluation of anti-thyroid auto-antibodies.
No significant differences between the two groups of old subjects was found for both FT4 and FT3 serum levels, as well as for the incidence of auto-antibodies positivity. On the contrary, the serum TSH concentration was significantly lower in centenarians than in healthy old and young controls. Furthermore, the FT3/FT4 ratio, a marker of the 5’-desjodase activity, had significantly lower values in elderly subjects and even more in centenarians than in young controls. Besides, higher levels of rT3 in centenarians than in both old and young controls were found, confirming the impairment of the 5’desjodinating activity. The decline of this enzymatic activity in centenarians may have different explanations, such as the effect of age itself or a reduced stimulatory activity of TSH, or even an age-related increase of inflammatory cytokines. On the other hand, the enhanced production of rT3 could be related to non-thyroidal diseases or to malnutrition. However our centenarians, even though rather thinner than controls, did not exhibit significant pathological conditions or changes in biochemical markers of malnutrition.
In conclusion, our findings suggest that the extreme longevity did not significantly modify the pituitary-thyroid axis, in spite of peripheral changes of the thyroxine metabolism leading to an increase of rT3 production and a condition of energy conservation.
As population aging has become a worldwide phenomenon, the burden of the age-related neurodegenerative diseases is expected to increase dramatically in both developed and developing nations. Alzheimer's disease is the most common neurodegenerative disorder among old people. Prevention may represent an ideal solution to the challenge posed by this condition. Recent epidemiological studies have revealed a number of risk and protective factors that could influence occurrence of dementia including Alzheimer type dementia. We propose that an active and stimulating lifestyle in late life as well as an optimal control of vascular and other chronic diseases both at middle age and late life can be two possible intervention strategies to prevent or postpone the onset of the dementing disorders, and perhaps the other neurodegenerative disorders such as Parkinson's disease as well.
Acute inflammation is usually a self-limited life preserving response, triggered by pathogens and/or traumatic injuries. This transient response normally leads to removal of harmful agents and to healing of the damaged tissues. In contrast, unchecked or chronic inflammation can lead to persistent tissue and organ damage by activated leukocytes, cytokines, or collagen deposition. Excessive energy intake and adiposity cause systemic inflammation, whereas calorie restriction without malnutrition exerts a potent anti-inflammatory effect. As individuals accumulate fat and their adipocytes enlarge, adipose tissue undergoes molecular and cellular alterations, macrophages accumulate, and inflammation ensues. Overweight/obese subjects have significantly higher plasma concentrations of Creactive protein and several cytokines, including IL-6, IL-8, IL-18, and TNF-alpha. Experimental animals on a chronic CR regimen, instead, have low levels of circulating inflammatory cytokines, low blood lymphocyte levels, reduced production of inflammatory cytokines by the white blood cells in response to stimulation, and cortisol levels in the high normal range. Recent data demonstrate that CR exerts a powerful anti-inflammatory effect also in non-human primates and humans. Multiple metabolic and neuroendocrine mechanisms are responsible for the CR-mediated anti-inflammatory effects, including reduced adiposity and secretion of pro-inflammatory adipokines, enhanced glucocorticoid production, reduced plasma glucose and advanced glycation end-product concentrations, increased parasympathetic tone, and increased ghrelin production. Measuring tissue specific effects of CR using genomic, proteomic and metabolomic techniques in humans will foster the understanding of the complex biological processes involved in the anti-inflammatory and anti-aging effects of CR.
During the lifetime of an adult organism, stem cells face extrinsic and intrinsic aging. Mesenchymal stem cells (MSC) can be expanded in culture and the numbers of population doublings individual cell isolates accumulate before entering senescence, are thought to vary according to fitness and age of the donor, respectively. No molecular markers, which specifically reflect the degree of cellular aging in a population of MSC, are available to date. Employing a genomic approach, we noticed that the gene encoding leptin receptor (also termed OB-R) is differentially regulated in MSCs derived from aged donors as well as in MSCs that had been stressed due to cultivation under hyperoxic conditions. We further revealed that leptin receptor transcript levels in primary MSC isolates inversely correlated with the prospective number of generations that are ahead of these cells in culture. The MSC subpopulation, which exhibited distinctly elevated levels of leptin receptor or CD295 at the cell surface, is indistinguishable from dying cells. Considered together with the observation that primary MSCs derived from healthy individuals showed proliferation capacities that declined at differentially increasing rates, we concluded that attenuation of MSCs’ proliferation potential during aging greatly relies on the strictly increasing withdrawal of cells due to cell death.
Kuru was the first human neurodegenerative disease in the group of transmissible spongiform encephalopathies, prion diseases or, in the past, slow unconventional virus diseases. It was reported to Western medicine in 1957 by D. Carleton Gajdusek and Vincent Zigas. Kuru was spread by endocannibalism and because of this the ratio of affected women and children to men was excessive. The hallmark of kuru neuropathology is the amyloid plaque.
We may speculate what would happen if kuru had not been discovered or did not exist. The infectious nature of Creutzfeldt-Jakob disease would probably not have been suspected until the beginning of the vCJD outbreak in the UK. Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease would have remained for decades as obscure neurodegenerations of merely academic interest. The familial forms of Creutzfeldt-Jakob disease would not have benefited from PRNP gene analysis, but only later would have been studied by linkage analysis and reverse genetics probably. The whole field would have probably remained of only arcane interest to veterinarians until the BSE epidemic began to exert its devastating effect. The discovery of vCJD would have been delayed, as no surveillance would have been initiated for Creutzfeldt-Jakob disease. And perhaps most importantly, the sea-change in mentality that has led to the conception of 'protein-misfolding diseases', including not only the neurodegenerative but also an increasing number of non-neurological disorders, would have been delayed by decades.
Our studies in yeast have shown that the down-regulation of the Ras2 or Sch9 pathways increases stress resistance and causes an up to 10-fold chronological life span extension. Whereas other laboratories have proposed that Sir2 and its homologs can extend longevity in various model organisms we proposed that Sir2 can also accelerate cellular aging and death. In S. cerevisiae the deletion of SIR2 increases DNA damage but in combination with longevity mutations in the Ras/cAMP or Sch9 pathway or in combination with calorie restriction causes a further increase in the chronological life span as well as increased stress resistance and a major reduction in age-dependent genomic instability. Our recent results also provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the activation of the insulin/IGF-I/Ras/ERK1/2 neuronal pathway and in the sensitization of neurons to oxidative damage. However, the mean life span of the SirT1+/– mice was not different from that of wild type animals and the survival of SirT1–/– mice was reduced under both normal and calorie restricted conditions. Here, I review studies linking SirT1, IGF-I signaling and starvation in various model organisms with focus on post-mitotic cells, which indicate that sirtuins can play both protective and pro-aging roles.
The function of adult stem cells declines during aging and chronic diseases. An understanding of the molecular mechanisms underlying these processes will help to identify targets for future therapies aiming to improve regenerative reserve and organ maintenance. Telomere shortening represents a cell intrinsic mechanism inducing DNA damage in aging cells. Current studies in telomerase knockout mice have shown that telomere dysfunction induces cell intrinsic checkpoints and environmental alteration that limit stem cell function. These phenotypes differ from wildtype mice with long telomere reserves, but they appear to be relevant for human aging, which is associated with an accumulation of telomere dysfunction and DNA damage.
It is generally agreed that taller people are
healthier and live longer than shorter people.
The findings presented to support the “taller is better”
thesis often ignores the robust evidence
that the opposite is true. My presentation will
focus on this contrary evidence and will include
data that shorter people of lean to moderate weight
actually have less cancer, coronary heart disease, and all-cause mortality.
In addition, data will be presented to show that the difference in
male-female life expectancy closely tracks the difference in young
adult height between the genders. Other findings will include several studies
that have found taller people have reduced life spans compared to
shorter ones, including a study of 1.3 million men tracked over a 70-y period.
A study of identical and fraternal twins will show that the smaller identical
twins have greater longevity compared to bigger fraternal twins.
Another topic includes the finding that shorter populations in
the developed world rank highest in life expectancy compared to the
tallest European countries. Findings will also show that centenarians
are often very short. Robust findings from the animal and plant
world will also show that within the same species, smaller lives longer.
Another topic includes confounding factors which may explain discrepant findings.
In addition, biological mechanisms are given to explain why smaller
bodies tend to have less chronic disease and longer lifespans.
Age-associated changes in the relative levels of sex steroid hormones and paracrine/autocrine growth factors (particularly decreasing androgens and increasing transforming growth factor beta, TGFb) promote stromal tissue remodelling and fibroblast-to-myofibroblast transdifferentiation, a characteristic feature of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common disease affecting elderly males.
In vitro models of fibroblast-to-myofibroblast transdifferentiation implicate an interwoven network of (i) local changes in androgen metabolism and signalling, (ii) alterations in the IGF axis and (iii) signalling through reactive oxygen species (ROS). Specifically, we show that the TGFb signal in primary prostatic stromal fibroblasts (PrSCs) is transduced via NADPH oxidase 4-produced ROS, which by regulating the activity of distinct mitogen-associated protein kinases determines the downstream transcriptional response to TGFb. Of the numerous components of the IGF axis that are regulated during transdifferentiation, the most striking change is elevated IGFBP3 secretion. Whilst stimulation of PrSCs with IGFBP3 alone does not induce transdifferentiation, costimulation assays indicate a synergistic response between TGFb and IGFBP3. Thus, by inhibiting cellular proliferation, IGFBP3 may sensitize fibroblasts to transdifferentiation signals.
During transdifferentiation, altered expression of several enzymes involved in androgen metabolism suggest enhanced bioactive androgen production, perhaps as a protective effect against the apoptosis-inducing activity of TGFb and may account at least in part for preserved intra-prostatic androgen levels despite age-related decreasing systemic concentrations. Moreover, androgens produced by the remodelled stroma may facilitate PCa progression to androgen independence even after endocrine treatment. Reciprocal crosstalk between Androgen Receptor (AR) signalling and growth factors (including TGFb) serves to modulate the downstream cellular response, which is determined by the relative ratio of receptor intermediates and cofactors. IGFBP3 induce expression of a selective AR repressor, Prostate Associated Gene 4 (PAGE4), indicating that specific aspects of AR signalling may be negatively modulated (most likely in a promoter-specific manner) during transdifferentiation.
In summary, we report an integrated network of changes in growth factor and androgen signalling/metabolism in the prostatic stroma during fibroblast-to-myofibroblast transdifferentiation with implications for the onset and progression of age-associated prostatic disease.
This work is supported by Austrian Science Fund (NRN 93B05). NS is the recipient of a Lise Meitner Scholarship (M903-B05).
In higher organisms dependent on the regenerative ability of tissue stem cells to maintain tissue integrity throughout adulthood, the failure of stem cells to replace worn out, dead, or damaged cells is seen as one mechanism that limits lifespan. In these organisms, tumor suppressors such as p53 are central participants in the control of longevity because they regulate stem cell proliferation. Several recent reports have identified p53 as a longevity gene in organisms such as C. elegans and Drosophila melanogaster, which lack proliferative stem cells in all but the germline and have relatively short lifespans. This has forced us to reevaluate the role of p53 in the control of lifespan. We discuss how p53 might regulate longevity in both long- and short-lived species by controlling the activity of insulin-like molecules that operate in proliferating and non-proliferating compartments of adult somatic tissues. We also discuss the hierarchical structure of lifespan regulation where loss of p53 has lifespan extending effects. Finally, we suggest a molecular mechanism by which p53 might facilitate the response to severe nutrient deprivation that allows metabolically active cells to survive periods of starvation. Paradoxically, loss of p53 function in these cells would compromise lifespan.
Aging is associated with a progressive decline of muscle mass, strength, and quality, a condition described as sarcopenia of aging. Despite the significance of skeletal muscle atrophy, the mechanisms responsible for the deterioration of muscle performance are only partially understood. The purpose of this review is to highlight cellular, molecular and biochemical changes that contribute to age-related muscle weakness.
Mitochondria play a critical role in the life of the cell as they control their metabolic rate, energy production and cell death. Mitochondria have long been appreciated as causative to ageing. The age-associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA-mutator mice has provided the first direct evidence that accelerating the mtDNA mutation rate can result in premature ageing, consistent with the view that loss of mitochondrial function is a major causal factor in ageing. New, controversial data have arisen from the studies on molecular mechanisms that drive premature ageing in mtDNA mutator mice. Our results suggest that the accumulation of high levels of mtDNA point mutations, mainly in protein coding genes, combined with their clonal expansion is probably the main driving force behind premature ageing in mtDNA mutator mice.
With the increasing emphasis on vascular disease as a risk factor for dementia and cognitive impairment, lowering cholesterol has received much attention to maintain cognitive function. Observational studies have shown that high total serum cholesterol levels in middle age, but not in old age, associate with cognitive impairment in later life. This can in part be explained as the association between high levels of total serum cholesterol levels and cardiovascular disease becomes weaker with increasing age and is absent in old age. Most studies on HDL-cholesterol levels show a protective association with cardiovascular disease up to old age, whereas data on the protective association with late-life cognitive impairment is absent. In contrast to general belief, randomized controlled trials and most longitudinal observational studies do not show a positive effect of statin treatment on the risk of dementia when prescribed in later life. In conclusion, high total serum cholesterol in middle age is associated with cognitive impairment and statin therapy is likely to have a benefit on cognitive function via a decrease of cardiovascular pathologies. A beneficial effect of cholesterol lowering in old age is uncertain.