Aging, cancer, and cancer vaccines

ABSTRACT: World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people 1. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 2. Further, cancer-related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older 3. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression.     

免疫基因多态性与衰老和增龄相关疾病关系

衰老是进行性的、多细胞普遍存在的、不可逆的功能减退状态。免疫衰老主要表现为造血干细胞再生和淋巴系分化能力下降、机体对感染和疫苗的反应减弱、对炎症反应的放大和自身的免疫反应增加, 与衰老和增龄相关疾病密切相关。免疫基因变异, 影响机体免疫反应, 可加速或延缓衰老和增龄相关疾病。获得性免疫基因, 如对自身免疫性疾病起保护性作用的HLA II 抗原基因DRB1*11和DRB*16相关的单倍型在长寿老人频率增加。抗炎因子IL-10-1082G等位基因频率和TGFβ1单倍型cnd10T/C、cnd25G/G、-988C/C、-800G/A频率的下降, 促炎因子TNFα低表达相关的扩展的TNF-A基因型-1031C/C、-863C/A、-857C/C、IL-6-174 CC基因型, 和IFN-γ+874 T等位基因频率减少与免疫炎症反应易感性, 衰老相关疾病的发病率和死亡率正相关。固有免疫基因, 如高频表达抗炎的+896 G KIR4等位基因、CCR5Δ32突变、-765 C Cox-2等位基因、-1708 G和21 C 5-Lox等位基因多见于长寿老人。KIR 单倍型 KIR2DS5、A1B10减少, MBL2表达缺乏的单倍型LYPB、LYQC 和HYPD增加的老年人常伴有较高血清CMV抗体滴度。高频出现的CRP ATG单倍型和CFH 402 His 等位基因预示老年人高死亡率风险。文章对固有和获得性免疫基因多态性、单倍体与衰老及衰老相关疾病关系进展进行综述。加强分析扩展的单倍型、表观遗传学和造血干细胞衰老的遗传学研究将有助于更好地理解衰老和长寿的免疫遗传学基础。     

Central mechanisms of the development of motor disorders during human aging

This paper deals with the functional state of the brain and its descending regulatory influences on the brain stem-spinal formations in the elderly. The role of changes revealed in the formation of the clinical syndrome of age-related extrapyramidal insufficiency (EPI) as a risk factor of Parkinson's disease, has been shown. 274 apparently healthy subjects aged from 20 to 102 and 136 patients with early stages of Parkinson's disease were examined. The program of the neurophysiological investigation included: frequency-integrative analysis of EEG, visual and somatosensory potentials, simple motor reaction time and stimulating electroneuromyography (H reflex). It has been found that in aging and in Parkinson's disease one-directional changes in the CNS function that form age-related and pathologic EPI occur. The complex of neurophysiological indices is a reflection of the CNS influence on the underlying spinal formations, and it can be used for early diagnostics of the motor disorders in aging.     

Age-related and seasonal variation in the Sertoli cell population, daily sperm production and serum concentrations of follicle-stimulating hormone, luteinizing hormone and testosterone in stallions

Testes and blood samples were obtained from 201 stallions aged 6 months to 20 years in either December-January (nonbreeding season) or June-July (breeding season) to study the effect of age and season on reproductive parameters. Seasonal differences in the Sertoli cell population of adult (4-20 years old) horses were characterized by a 36% larger number of Sertoli cells in the breeding season than in the nonbreeding season. Seasonal elevation in the Sertoli cell population was associated with an increase in testicular weight and daily sperm production per testis (DSP/testis). Concentrations of luteinizing hormone (LH) and testosterone in serum varied with season. Although follicle-stimulating hormone (FSH) concentrations also tended to be higher in the breeding season, this trend was not statistically significant (P less than 0.08). Sertoli cell numbers averaged over both seasons, like testicular weights, increased with age until 4-5 years of age, but were stabilized thereafter. This age-related difference was also associated with increased concentrations of FSH, LH and testosterone, and with increased DSP/testis. The Sertoli cell population was capable of increasing in the adult horse by fluctuating its size with season. The number of elongated spermatids per Sertoli cell over both seasons increased with age up to 4-5 years of age and was stabilized thereafter. Thus, seasonal and/or age-related differences in DSP/testis were associated with significant elevations in serum concentrations of FSH, LH and testosterone, testicular weights, numbers of elongated spermatids per Sertoli cell and elevation of the Sertoli cell population.     

Aging and cardioprotection.

Advanced age is a strong independent predictor for death, disability, and morbidity in patients with structural heart disease. With the projected increase in the elderly population and the prevalence of age-related cardiovascular disabilities worldwide, the need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability, and the development of strategies to limit myocardial dysfunction in the elderly have never been more urgent. Experimental evidence in animal models indicate attenuation in cardioprotective pathways with aging, yet limited information is available regarding age-related changes in the human heart. Human cardiac aging generates a complex phenotype, only partially replicated in animal models. Here, we summarize current understanding of the aging heart stemming from clinical and experimental studies, and we highlight targets for protection of the vulnerable senescent myocardium. Further progress mandates assessment of human tissue to dissect specific aging-associated genomic and proteomic dynamics, and their functional consequences leading to increased susceptibility of the heart to injury, a critical step toward designing novel therapeutic interventions to limit age-related myocardial dysfunction and promote healthy aging.     

Stress responses and innate immunity: aging as a contributory factor

Evolutionary pressure has selected individuals with traits that allow them to survive to reproduction, without consideration of the consequences for the post-child rearing years and old age. In the 21st century, society is populated increasingly by the elderly and with the falling birth rate and improved health care this trend is set to continue for the foreseeable future. To minimize the potential burden on health services one would hope that 'growing old gracefully' should also mean 'growing old healthily'. However, for too many the aging process is accompanied by increasing physical and mental frailty producing an elevated risk of physical and psychological stress in old age. Stress is a potent modulator of immune function, which in youth can be compensated for by the presence of an optimal immune response. In the elderly the immune response is blunted as a result of the decline in several components of the immune system (immune senescence) and a shifting to a chronic pro-inflammatory status (the so-called 'inflamm-aging' effect). We discuss here what is known of the effects of both stress and aging upon the innate immune system, focusing in particular upon the age-related alterations in the hypopituitary-adrenal axis. We propose a double hit model for age and stress in which the age-related increase in the cortisol/sulphated dehydroepiandrosterone ratio synergizes with elevated cortisol during stress to reduce immunity in the elderly significantly.     

Melatonin and mitochondria in aging

The worldwide prolongation of mean life expectancy has resulted in a rapid increase of the size of the elderly population, both in numbers and as a proportion of the whole. In addition, the incidence of age-related diseases is obviously increasing as the population ages. Finding means to preserve optimal health in old age has become a primary goal of biomedical research. Aging is a multifactorial process that includes progressive cellular loss, endocrine and metabolic deficits, reduced defense mechanisms and functional losses that increase the risk of death. Mitochondria fulfill a number of essential cellular functions and play a key role in the aging process. Melatonin, which is synthesized in the pineal gland and other organs, plays a role in the biologic regulation of aging. Noctural melatonin serum levels are high during childhood and diminish substantially as people age. Melatonin preserves mitochondrial homeostasis, reduces free radical generation, e.g., by enhancing mitochondrial glutathione levels; it also safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. In this article, we review the role of melatonin and mitochondria in aging.     

Age-related changes in immunity: implications for vaccination in the elderly

Average life expectancy is continuously rising in all developed countries, leading to an ever-increasing elderly population. Of the many functions of the body affected by the complex process of ageing, the immune system in particular undergoes various changes, collectively termed immunosenescence. As a result, elderly people are more susceptible to infections and are frequently less protected by vaccines. This review summarises the effect of ageing on immunity, emphasising the age-associated changes within T and B cells at a molecular and cellular level. Furthermore, it discusses strategies, such as the addition of immunostimulatory adjuvants and the use of potent antigen-delivery systems, that may counteract age-related defects in immune responses to vaccination. A proper understanding of how immunological memory is affected by ageing, and the introduction of strategies to ameliorate vaccine efficacy in the elderly, might reduce the incidence and the severity of infectious disease within this fragile age group and have a strong impact on the quality of life of elderly individuals.     

Immunological aspects of age-related diseases

The proportion of elderly people rises in the developed countries. The increased susceptibility of the elderly to infectious diseases is caused by immune dysfunction, especially T cell functional decline. Age-related hematopoietic stem cells deviate from lymphoid lineage to myeloid lineage. Thymus shrinks early in life, which is followed by the decline of na?ve T cells. T-cell receptor repertoire diversity declines by aging, which is caused by cytomegalovirus-driven T cell clonal expansion. Functional decline of B cell induces antibody affinity declines by aging. Many effector functions including phagocytosis of myeloid cells are down regulated by aging. The studies of aging of myeloid cells have some controversial results. Although M1 macrophages have been shown to be replaced by antiinflammatory(M2) macrophages by advanced age, many human studies showed that pro-inflammatory cytokines are elevated in older human. To solve this discrepancy here we divide age-related pathological changes into two categories. One is an aging of immune cell itself. Second is involvement of immune cells to age-related pathological changes. Cellular senescence and damaged cells in aged tissue recruit pro-inflammatory M1 macrophages, which produce pro-inflammatory cytokines and proceed to agerelated diseases. Underlying biochemical and metabolic studies will open nutritional treatment.     

Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses

Little is known about the effects of aging on the hepatic drug metabolizing capacity of horses despite the relatively long lifespan characterizing this species. A wide array of cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases were assayed in liver microsomes from 50 female horses in an age range between less than 1 year to over 12 years. Rather unexpectedly, both the CYP content and the activity of NADPH cytochrome c reductase rose as a function of age. Accordingly, a general increasing trend was recorded in the rate of the in vitro metabolism of the substrates reported to be related to CYP2B-, CYP2E- or CYP3A, although, as detected by Western immunoblotting, only the levels of proteins recognized by anti-rat CYP3A- and CYP2B antibodies appeared to increase consistently. Also the carboxylesterases and uridindiphosphoglucuronyl-transferase (UGT) activity toward 1-naphthol displayed a similar trend, glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate being the only enzyme activity showing an age-related decline. A positive correlation was also found between liver cadmium content and CYP amount as well as the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT. While confirming that a number of enzyme activities are less expressed in foals, our results contradict the general view that the drug metabolizing capacity drops in elder individuals. Although several other factors can influence the kinetics of foreign compounds in aged animals, data from this study may provide insight in understanding possible age-related differences in drug efficacy and the response to toxic substances in horses.     

Age-Related Patterns in Human Myeloid Dendritic Cell Populations in People Exposed to Schistosoma haematobium Infection

Background

Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium. In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood. This age-related infection profile is thought to result from the gradual development of protective acquired immunity. Age-related differences in schistosome-specific humoral and cellular responses have been reported from several field studies. However there has not yet been a systematic study of the age-related changes in human dendritic cells, the drivers of T cell polarisation.

Methods

Peripheral blood mononuclear cells were obtained from a cohort of 61 Zimbabwean aged 5–45 years with a S. haematobium prevalence of 47.5%. Two subsets of dendritic cells, myeloid and plasmacytoid dentritic cells (mDCs and pDCs), were analyzed by flow cytometry.

Findings

In this population, schistosome infection levels peaked in the youngest age group (5–9 years), and declined in late childhood and adulthood (10+ years). The proportions of both mDCs and pDCs varied with age. However, for mDCs the age profile depended on host infection status. In the youngest age group infected people had enhanced proportions of mDCs as well as lower levels of HLA-DR on mDCs than un-infected people. In the older age groups (10–13 and 14–45 years) infected people had lower proportions of mDCs compared to un-infected individuals, but no infection status-related differences were observed in their levels of HLA-DR. Moreover mDC proportions correlated with levels of schistosome-specific IgG, which can be associated with protective immunity. In contrast proportions of pDCs varied with host age, but not with infection status.

Conclusions

Our results show that dendritic cell proportions and activation in a human population living in schistosome-endemic areas vary with host age reflecting differences in cumulative history of exposure to schistosome infection.     

Aging and insulin secretion

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting beta-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, beta-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired beta-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.     

Mental distress and social conditions and lifestyle in northern Norway.

In a cross sectional survey of risk factors for coronary heart disease three questions about mental distress were included in a questionnaire completed by 13,704 people, 64% of the total population aged 20-54 in one municipality. Overall, 860 (12.5%) of the men and 1141 (16.8%) of the women reported having at least one symptom of mental distress. There were no distinct differences between the age groups. Single people, separated and divorced people, and those who reported that the financial situation of the family during their childhood was difficult reported more mental problems. Heavy smoking, frequent alcohol consumption, and, in men, little or no physical activity in leisure time were also associated with a high prevalence of mental distress. By multiple regression analyses, marital state, financial situation of family during childhood, and current lifestyle were found to be highly significantly associated with mental distress. Including a few questions on mental distress in health surveys provides a way to establish relations between such symptoms and social conditions and lifestyle in large numbers of subjects.     

Aging impacts isolated lymphoid follicle fevelopment and function

Background  

Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. The majority of studies have focused on immunosenescence in the systemic immune system; information concerning the effect of aging on intestinal immunity is limited. Isolated lymphoid follicles (ILFs) are newly appreciated dynamic intestinal lymphoid structures that arise from nascent lymphoid tissues, or cryptopatches (CP), in response to local inflammatory stimuli. ILFs promote "homeostatic" responses including the production of antigen-specific IgA, thus playing a key role in mucosal immune protection. ILF dysfunction with aging could contribute to immunosenescence of the mucosal system, and accordingly we examined phenotypic and functional aspects of ILFs from young (2 month old) and aged (2 year old) mice.     

Trends in use of medical services by the elderly in British Columbia.

We analysed physician fee-for-service use in British Columbia from 1974-75 to 1985-86. Over the study period use increased by 5.3% per year. This can be factored into increases attributable to changes in the age structure of the population (0.4% per year), general population growth (1.8%, for a combined annual "population effect" of 2.2%) and age-specific increases in per-capita use (3% per year). The average annual increase for people aged 75 years or more was 5.5% per capita. The area with the fastest growth in use by the elderly was specialist care, particularly diagnostic services. The average number of specialists seen by people aged 75 years or more doubled over the study period. Our results suggest that increased per-capita use among the elderly that is unrelated to aging of the population should be the main focus of future policy attention. Additional analyses are needed to determine the underlying dynamics of this dramatic increase in rates of use among the elderly.     

Age-Related Features of the Voluntary Control of the Upright Posture

The capability for the unconscious control of the upright posture in elderly people is impaired, which increases the risk of falls and traumata. The impairment of the unconscious control of posture is partially compensated by the fixation of voluntary attention on the maintenance of an appropriate posture. Elderly people fall predominantly during the performance of movements that demand additional voluntary postural control, for example, unstable support conditions. Thus, voluntary postural control assumes importance in elderly persons. Since it is unclear whether this function changes with age, the aim of this work was to study age-related features of the learning voluntary postural control using visual feedback by center-of-pressure position. The results of the study showed that voluntary postural control is a complex multicomponent process that includes, at least, the following functions: selection of a strategy of postural control, its actualization, and precision of its regulation. With aging, strategy selection in healthy people impairs, but both elderly and middle-aged people can learn this function as successfully as the young. At the same time, despite the absence of an initial deficit in the accuracy of postural setting in elderly people, training of this function becomes substantially more difficult with age.     

Orthostatic reactions of blood circulation and autonomic regulation in healthy persons of various ages

The age-related changes in vegetative regulation of blood circulation during active orthostatic test (AOT) have been studied in 90 practically healthy people aged from 21 to 89. The stroke blood volume was determined using the tetrapolar thoracic rheography. The basic state of the vegetative heart regulation and its changes during AOT were studied by means of the spectral analysis of the stationary rhythmograms. It is shown that intensity of both primary and secondary compensatory circulatory responses during the AOT decreases with age. An age-related impairment of the reflectory influences on heart and vessels is induced by a decreased overall vegetative tonus and insufficient activation of the sympathetic system in orthostasis. The orthostatic hypotension in elderly and old people is probably mediated by an inadequately small increment of peripheral vascular resistance and cardiac rhythm resulting from the age-related impairment of baroreceptor sympathetic control of the blood pressure.     

Diferencias en función de la edad y la autopercepción del envejecimiento en ansiedad,tristeza, soledad y sintomatología comórbida ansioso-depresiva durante el confinamiento por la COVID-19

ObjectivesTo analyze differences by age group in anxiety, depression, loneliness and comorbid anxiety and depression in young people, middle aged adults and older adults during the lock-down period at home due to the COVID-19 pandemic, and to explore the association between negative self-perceptions of aging and psychological symptoms controlling by age group.MethodParticipants are 1501 people (age range 18 to 88 years). Anxiety, sadness, loneliness and self-perceptions of aging were assessed. The sample was divided according to the age group and quartiles (lower, intermediate levels, and higher) of anxiety, sadness, loneliness and self-perceptions of aging.ResultsOlder adults reported lower levels of anxiety and sadness than middle aged adults, and middle aged adults reported lower levels than younger participants. Middle aged adults reported the lowest loneliness, followed by older adults and younger participants. For each age group, those with more negative self-perceptions of aging reported higher anxiety, sadness and loneliness. More comorbid anxiety and sadness was found in younger adults and less in older adults; more depressed participants in the middle aged group, and more older adults and less younger participants were found in the group with the lowest levels of anxiety and sadness. For all the age groups, participants with high levels of comorbid anxiety and sadness are those who report the highest scores in negative self-perceptions of aging.ConclusionsOlder adults reported lower psychological anxiety, sadness and loneliness than the other age groups. Having negative self-perceptions of aging damage psychological health irrespective of the chronological age.     

Rectification of age-associated deficiency in cytotoxic T cell response to influenza A virus by immunization with immune complexes

Decline in cellular immunity in aging compromises protection against infectious diseases and leads to the increased susceptibility of the elderly to infection. In particular, Ag-specific cytotoxic T lymphocyte (CTL) response against virus is markedly reduced in an aged immune system. It is of great importance to explore novel strategy in eliciting effective antiviral CTL activity in the elderly. In this study, the efficacy and mechanisms of immunization with immune complexes in overcoming age-associated deficiency in cellular immunity were investigated. In this study, we show that the severely depressed CTL response to influenza A in aged mice can be significantly restored by immunization with immune complexes consisting of influenza A virus and mAb to influenza A nucleoprotein. The main mechanisms underlying this recovery of CTL response induced by immune complex immunization in aged mice are enhanced dendritic cell function and elevated production of IFN-gamma in both CD4(+) Th1 and CD8(+) CTLs. Thus, these results demonstrate that immune complex immunization may represent a novel strategy to elicit effective virus-specific cytotoxic response in an aged immune system, and possibly, to overcome age-related immune deficiency in general.