Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan

Large, long-lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short-lived species. Large, long-lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, in rodents: telomerase activity is repressed in the somatic tissues of large rodent species but remains active in small ones. Without telomerase activity, the telomeres of replicating cells become progressively shorter until, at some critical length, cells stop dividing. Our findings therefore suggested that repression of telomerase activity mitigates the increased risk of cancer in larger-bodied species but not necessarily longer-lived ones. These findings imply that other tumor suppressor mechanisms must mitigate increased cancer risk in long-lived species. Here, we examined the proliferation of fibroblasts from 15 rodent species with diverse body sizes and lifespans. We show that, consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16(Ink4a) and p21(Cip1/Waf1) cycline-dependent kinase inhibitors. Interestingly, small rodents with different lifespans show a striking difference: cells from small shorter-lived species display continuous rapid proliferation, whereas cells from small long-lived species display continuous slow proliferation. We hypothesize that cells of small long-lived rodents, lacking replicative senescence, have evolved alternative tumor-suppressor mechanisms that prevent inappropriate cell division in vivo and slow cell growth in vitro. Thus, large-bodied species and small but long-lived species have evolved distinct tumor suppressor mechanisms.

Novel foods across the lifespan: From infant formula to impact on ageing

The purpose of the present paper was to examine the scope of novel foods in improving and/or preventing the nutritional disorders in different stages of lifespan. First, attempts were made to review the current trend and magnitude of the nutritional problems in each of the stages starting from fetal development to old age. The paper then describes the possible potential role of novel foods in alleviating and/or preventing these nutritional/health problems. The conclusion made is that the novel foods have a great potential for improving the overall nutritional status throughout the lifespan, thereby reducing the risk of early death or disability due to chronic diseases. However, to achieve a noticeable impact of novel foods on public health, efforts are needed to ensure that these foods are available and affordable to the population most at risk.

Managing urinary incontinence across the lifespan

In the 1996 baseline surveys of the Australian Longitudinal Study of Women's Health (ALSWH), 36.1% of mid-age women (45-50) and 35% of older women (70-75) reported leaking urine. This study aimed to investigate (a) the range of self-management strategies used to deal with urinary incontinence (UI); (b) the reasons why many women who report leaking urine do not seek help for UI; and (c) the types of health professionals consulted and treatment provided, and perceptions of satisfaction with these, among a sample of women in each age group who reported leaking urine often' at baseline. Five hundred participants were randomly selected from women in each of the mid-age and older cohorts of the ALSWH who had reported leaking urine often in a previous survey. Details about UI (frequency, severity, and situations), self-management behaviors and help-seeking for UI, types of health professional consulted, recommended treatment for the problem, and satisfaction with the service provided by health care professionals and the outcomes of recommended treatments were sought through a self-report mailed follow-up survey. Most respondents had leaked urine in the last month (94% and 91% of mid-age and older women, respectively), and 72.2% and 73. 1% of mid-aged and older women, respectively, had sought help or advice about their UI. In both age groups, the likelihood of having sought help significantly increased with severity of incontinence. The most common reasons for not seeking help were that the women felt they could manage the problem themselves or they did not consider it to be a problem.. Many women in both cohorts had employed avoidance techniques in an attempt to prevent leaking urine, including reducing their liquid consumption, going to the toilet just in case, and rushing to the toilet the minute they felt the need to. Strategies are needed to inform women who experience UI of more effective management techniques and the possible health risks associated with commonly used avoidance behaviors. There may be a need to better publicize existing incontinence services and improve access to these services for women of all ages.

Urinary incontinence across the lifespan

Aims: The objectives of the current study were (1) to measure type and severity of urinary leakage and (2) to investigate the association between these factors and age-related life events and conditions in three groups of Australian women with a history of urinary leakage. Methods: Five hundred participants were randomly selected from women in the young (aged 18-22 in 1996), mid-age (4550),and older (70-75) cohorts of the Australian Longitudinal Study of Women's Health (ALSWH) who had reported leaking urine in the 1996 baseline survey. Details about leaking urine (frequency, severity, situations) and associated factors (pregnancy, childbirth, body mass index [BMI]) were sought through self-report mailed follow-up surveys in 1999. Results & Conclusions: Response rates were 50, 83, and 80% in the young, mid-age, and older women, respectively. Most women confirmed that they had, leaked urine in the past month, and the majority of these were cases of mixed incontinence. Incontinence severity tended to increase with BMI for women of all ages, and increased severity scores were associated with having urine that burns or stings. Additional independent risk factors for increasing incontinence severity were heavy smoking in young women, past or present use of hormone replacement therapy in older women, and BMI and history of hysterectomy in mid-age women. (C) 2003 Wiley-Liss, Inc.

The mental health of young people in Ireland:a report of the Psychiatric Epidemiology Research across the Lifespan (PERL) Group Dublin.

There has been a dearth of epidemiological research on rates of mental disorder among Irish people and little is known about the numbers of young people in Ireland who are experiencing diagnosable mental disorders. In the context of such limited epidemiological research in the field of mental health, the PERL Group in the Royal College of Surgeons in Ireland has conducted two studies on mental disorders and psychopathology among young Irish people. This report is the first research report from these two studies by the PERL Group. It provides data on the prevalence rates of mental disorder, substance use, deliberate self-harm and suicidality among young Irish people aged 11-24 years.This resource was contributed by The National Documentation Centre on Drug Use.

Lifespan extension by calorie restriction relies on the Sty1 MAP kinase stress pathway

Either calorie restriction, loss of function of the nutrient-dependent PKA or TOR/SCH9 pathways, or activation of stress defences improves longevity in different eukaryotes. However, the molecular links between glucose depletion, nutrient-dependent pathways and stress responses are unknown. Here we show that either calorie restriction or inactivation of nutrient-dependent pathways induces life-span extension in fission yeast, and that such effect is dependent on the activation of the stress-dependent Sty1 MAP kinase. During transition to stationary phase in glucose-limiting conditions, Sty1 becomes activated and triggers a transcriptional stress program, whereas such activation does not occur under glucose-rich conditions. Deletion of the genes coding for the SCH9-homologue Sck2 or the Pka1 kinases, or mutations leading to constitutive activation of the Sty1 stress pathway increase life span under glucose-rich conditions, and importantly such beneficial effects depend ultimately on Sty1. Furthermore, cells lacking Pka1 display enhanced oxygen consumption and Sty1 activation under glucose-rich conditions. We conclude that calorie restriction favours oxidative metabolism, reactive oxygen species production and Sty1 MAP kinase activation, and this stress pathway favours life-span extension.

Plasticity of lifespan: a reaction norm perspective.

It is a well-appreciated fact that in many organisms the process of ageing reacts highly plastically, so that lifespan increases or decreases when the environment changes. The perhaps best-known example of such lifespan plasticity is dietary restriction (DR), a phenomenon whereby reduced food intake without malnutrition extends lifespan (typically at the expense of reduced fecundity) and which has been documented in numerous species, from invertebrates to mammals. For the evolutionary biologist, DR and other cases of lifespan plasticity are examples of a more general phenomenon called phenotypic plasticity, the ability of a single genotype to produce different phenotypes (e.g. lifespan) in response to changes in the environment (e.g. changes in diet). To analyse phenotypic plasticity, evolutionary biologists (and epidemiologists) often use a conceptual and statistical framework based on reaction norms (genotype-specific response curves) and genotype × environment interactions (G × E; differences in the plastic response among genotypes), concepts that biologists who are working on molecular aspects of ageing are usually not familiar with. Here I briefly discuss what has been learned about lifespan plasticity or, more generally, about plasticity of somatic maintenance and survival ability. In particular, I argue that adopting the conceptual framework of reaction norms and G × E interactions, as used by evolutionary biologists, is crucially important for our understanding of the mechanisms underlying DR and other forms of lifespan or survival plasticity.

Loss of Memo, a novel FGFR regulator, results in reduced lifespan.

Memo is a widely expressed 33-kDa protein required for heregulin (HRG)-, epidermal growth factor (EGF)-, and fibroblast growth factor (FGF)-induced cell motility. Studies in mouse embryonic fibroblasts, wild-type or knockout for Memo, were performed to further investigate the role of Memo downstream of FGFR. We demonstrated that Memo associates with the FGFR signalosome and is necessary for optimal activation of signaling. To uncover Memo's physiological role, Memo conditional-knockout mice were generated. These animals showed a reduced life span, increased insulin sensitivity, small stature, graying hair, alopecia, kyphosis, loss of subcutaneous fat, and loss of spermatozoa in the epididymis. Memo-knockout mice also have elevated serum levels of active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), and calcium compared to control littermates expressing Memo. In summary, the results from in vivo and in vitro models support the hypothesis that Memo is a novel regulator of FGFR signaling with a role in controlling 1,25(OH)2D production and normal calcium homeostasis.

Dietary restriction affects lifespan but not cognitive aging in Drosophila melanogaster.

Summary Dietary restriction extends lifespan in a wide variety of animals, including Drosophila, but its relationship to functional and cognitive aging is unclear. Here, we study the effects of dietary yeast content on fly performance in an aversive learning task (association between odor and mechanical shock). Learning performance declined at old age, but 50-day-old dietary-restricted flies learned as poorly as equal-aged flies maintained on yeast-rich diet, even though the former lived on average 9 days (14%) longer. Furthermore, at the middle age of 21 days, flies on low-yeast diets showed poorer short-term (5 min) memory than flies on rich diet. In contrast, dietary restriction enhanced 60-min memory of young (5 days old) flies. Thus, while dietary restriction had complex effects on learning performance in young to middle-aged flies, it did not attenuate aging-related decline of aversive learning performance. These results are consistent with the hypothesis that, in Drosophila, dietary restriction reduces mortality and thus leads to lifespan extension, but does not affect the rate with which somatic damage relevant for cognitive performance accumulates with age.

Antagonistic functions of LMNA isoforms in energy expenditure and lifespan.

Alternative RNA processing of LMNA pre-mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson-Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging. Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. In contrast, progerin-expressing mice show increased energy metabolism and are lipodystrophic. Increased mitochondrial biogenesis is found in adipose tissue from HGPS-like mice, whereas lamin C-only mice have fewer mitochondria. Consistently, transcriptome analyses of adipose tissues from HGPS and lamin C-only mice reveal inversely correlated expression of key regulators of energy expenditure, including Pgc1a and Sfrp5. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.