Senescent Pathologies Research Articles

Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

C. elegans ageing is accelerated by a self-destructive reproductive programme

In post-reproductive C. elegans, destructive somatic biomass repurposing supports production of yolk which, it was recently shown, is vented and can serve as a foodstuff for larval progeny. This is reminiscent of the suicidal reproductive effort (reproductive death) typical of semelparous organisms such as Pacific salmon. To explore the possibility that C. elegans exhibits reproductive death, we have compared sibling species pairs of the genera Caenorhabditis and Pristionchus with hermaphrodites and females. We report that yolk venting and constitutive, early pathology involving major anatomical changes occur only in hermaphrodites, which are also shorter lived. Moreover, only in hermaphrodites does germline removal suppress senescent pathology and markedly increase lifespan. This is consistent with the hypothesis that C. elegans exhibit reproductive death that is suppressed by germline ablation. If correct, this would imply a major difference in the ageing process between C. elegans and most higher organisms, and potentially explain the exceptional plasticity in C. elegans ageing.

Shelterin Complex at Telomeres: Implications in Ageing.

Different factors influence the development‎ and control of ageing. It is well known that progressive telomere shorting is one of the molecular mechanisms underlying ageing. The shelterin complex consists of six telomere-specific proteins which are involved in the protection of chromosome ends. More particularly, this vital complex protects the telomeres from degradation, prevents from activation of unwanted repair systems, regulates the activity of telomerase, and has a crucial role in cellular senescent and ageing-related pathologies. This review explores the organization and function of telomeric DNA along with the mechanism of telomeres during ageing, followed by a discussion of the critical role of shelterin components and their changes during ageing.

Age-dependent effects of floxuridine (FUdR) on senescent pathology and mortality in the nematode Caenorhabditis elegans

Floxuridine (5’-fluorodeoxyuridine, FUdR) acts as an inhibitor of DNA replication by binding to thymidylate synthase and is widely used to treat colorectal cancer. FUdR is also frequently used in research on aging in C. elegans since by blocking reproduction it allows maintenance of synchronous nematode populations. Here we examine age-specific effects of exposure to 50 μM FUdR on pathology and mortality. We report that initiating exposure to FUdR at late development or early adulthood reduces lifespan but later initiation increases it. Moreover, earlier initiation leads to enhancement of senescent intestinal atrophy, but amelioration of several other senescent pathologies (pharyngeal degeneration and uterine tumors). These results provide further evidence of the complex effects of FUdR on aging in C. elegans, and therefore support the argue against its routine use in studies of nematode aging due to its possible confounding effects. However, they also illustrate how effects of FUdR on aging are interesting in their own right.

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies

SummaryAging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C. elegans, a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis).

A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.

<i>C. Elegans</i> Eats Its Own Intestine to Make Yolk: A Cause of Senescent Polymorbidity

Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In Caenorhabditis elegans a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology, but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagymediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies, and can also extend lifespan. This defines a disease syndrome leading to polymorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation, but from continued action of a wild-type function (vitellogenesis), consistent with the recently proposed hyperfunction theory of aging.

Two forms of death in ageing Caenorhabditis elegans

Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age. Our results imply the presence of multiple causes of death. Specifically, we identify two classes of corpse: early deaths with a swollen pharynx (which we call ‘P deaths’), and later deaths with an atrophied pharynx (termed ‘p deaths’). The effects of interventions on lifespan can be broken down into changes in the frequency and/or timing of either form of death. For example, glp-1 mutation only delays p death, while eat-2 mutation reduces P death. Combining pathology and mortality analysis allows mortality profiles to be deconvolved, providing biological meaning to complex survival and mortality profiles.

Run-on of germline apoptosis promotes gonad senescence in C. elegans.

Aging (senescence) includes causal mechanisms (etiologies) of late-life disease, which remain poorly understood. According to the recently proposed hyperfunction theory, based on the older theory of antagonistic pleiotropy, senescent pathologies can arise from futile, post-reproductive run-on of processes that in early life promote fitness. Here we apply this idea to investigate the etiology of senescent pathologies in the reproductive system of Caenorhabditis elegans hermaphrodites, particularly distal gonad degeneration and disintegration. Hermaphrodite germ cells frequently undergo “physiological” (non-damage-induced) apoptosis (PA) to provision growing oocytes. Run-on of such PA is a potential cause of age-related gonad degeneration. We document the continuation of germline apoptosis in later life, and report that genetically blocking or increasing PA retards or accelerates degeneration, respectively. In wild-type males, which lack germ line apoptosis, gonad disintegration does not occur. However, mutational induction of PA in males does not lead to gonad disintegration. These results suggest that as germ-cell proliferation rate declines markedly in aging hermaphrodites (but not males), run-on of PA becomes a pathogenic mechanism that promotes gonad degeneration. This illustrates how hyperfunction, or non-adaptive run-on in later life of a process that promotes fitness in early life, can promote atrophic senescent pathology in C. elegans.

Microglial pathology in Down syndrome

Subjects with Down syndrome (DS) inevitably develop histopathological features pathognomonic of Alzheimer's disease (AD), and DS can therefore be considered a human model of AD. Similar to AD, microglial activation has been reported in DS and the idea that detrimental neuroinflammation plays a key role in the pathogenesis of neurodegeneration is firmly embedded. However, recent work from this laboratory has offered evidence for an alternative view regarding the role of microglial cells in AD pathogenesis by showing presence of dystrophic (senescent) rather than activated microglia in both the AD and DS brain. In this report, we build on previously published observations in human brain and offer a detailed analysis of microglial senescent pathology in the temporal cortices of 6 DS cases in their 40s, a critical age bracket where virtually all DS subjects acquire neurofibrillary degeneration characteristic of AD. Our findings using both Iba1 and anti-ferritin immunostaining of microglial cells show that coincident with the appearance of tau pathology in DS subjects there is consistent presence of dystrophic microglial cells and conspicuous absence of activated microglia using both markers. The extent of microglial pathology varied among the individual DS cases, but they all revealed decreased numbers of normal microglia ranging from 19 to 85% of the controls. Nearly all of the ferritin-positive microglia, which constitute a subset of the total Iba1-reactive microglial population, exhibited dystrophic morphology. In its most severe form dystrophy was evident as total fragmentation of the cells' cytoplasm (cytorrhexis), which likely reflects terminal degeneration of microglia. Severely dystrophic, ferritin-positive cells were often found to be colocalized with tau-positive senile plaques. Our findings help to consolidate the idea that microglial degeneration and neurofibrillary degeneration are closely linked events in a human model of AD. They suggest that microglial degeneration follows a gradually progressive course that increases in its severity in parallel with the progression of AD neurodegenerative changes.

Aging-associated changes in vascular activity: a potential link to geriatric cardiovascular disease.

Ischemic cardiovascular disease is a common cause of morbidity and mortality in the United States population over the age of 65. Prior clinical studies have demonstrated that the severity of cardiovascular pathophysiology is increased in older individuals. Both in vitro and in vivo experimental studies have shown that age-associated clinical events parallel changes in vascular function. Aging is associated with systemic as well as cardiac alterations in three basic vascular regulatory functions: vascular tone, hemostasis, and vascular repair/angiogenesis. This article reviews the molecular and cellular events that may contribute to senescent cardiac pathology. Indeed, a better understanding of the biology of aging-associated vascular dysfunction is fundamental for the development of therapeutics targeted for the treatment of cardiovascular disease in older individuals.

A review of autorefractors.

The overall performance of autorefractors in this study as defined by reliability, validity and rejection rate statistics, is similar to other hospital based studies but lower than in an optometric clinic. The performance of individual autorefractors varies according to the interaction between the underlying optical/detector mechanism and the media and pathological changes of a given eye. The autorefraction data proves a useful complement to the refractive data gained by conventional techniques, notwithstanding the poorer performance of the autorefractors in the presence of senescent pathology.

Senescent pathology of cerebellum: Purkinje neurons and their parallel fiber afferents

Two groups of naive male Sprague-Dawley rats, 5–7 and 24–26 months of age, were anesthetized with continuous intraperitoneal infusion of 4% chloral hydrate. Stimulation of the cerebellar vermis molecular layer permitted measurements of 12 different electrophysiological properties of parallel fiber/Purkinje cell circuitry: parallel fiber conduction velocity, refractory period, threshold, and current dependent volley amplitude; slow negative wave threshold and current dependent amplitude; Purkinje cell activation threshold, latency, and current dependent spike driving; and Purkinje cell inhibitory threshold, latency, and current dependent duration of inhibition. Old subjects demonstrated deficits on all parameters except Purkinje cell inhibitory threshold. The relevance of these findings to our previous research on senescent changes in cell number, lipofuscin deposition, and spontaneous firing of Purkinje cells is discussed.