Use of model organisms in aging research is problematic because our ability to extrapolate across the tree of life is not clear. On one hand, there are conserved pathways that regulate lifespan in ...organisms including yeast, nematodes, fruit flies, and mice. On the other, many intermediate taxa across the tree of life appear not to age at all, and there is substantial variation in aging mechanisms and patterns, sometimes even between closely related species. There are good evolutionary and mechanistic reasons to expect this complexity, but it means that model organisms must be used with caution and that results must always be interpreted through a broader comparative framework. Additionally, it is essential to include research on non-traditional and unusual species, and to integrate mechanistic and demographic research. There will be no simple answers regarding the biology of aging, and research approaches should reflect this. This article is part of a Special Issue entitled: Animal models of aging - edited by Houtkooper Riekelt.
•Many animals do not age, and physiological mechanisms of aging vary across species.•Nonetheless, conserved aging-related signalling pathways exist.•Aging is thus highly multi-factorial, complex, and particular to each species.•Animal models should include both traditional and non-traditional species.•Results should be interpreted cautiously and within a broad comparative perspective.
There have long been suggestions that aging is tightly linked to the complex dynamics of the physiological systems that maintain homeostasis, and in particular to dysregulation of regulatory networks ...of molecules. This review synthesizes recent work that is starting to provide evidence for the importance of such complex systems dynamics in aging. There is now clear evidence that physiological dysregulation—the gradual breakdown in the capacity of complex regulatory networks to maintain homeostasis—is an emergent property of these regulatory networks, and that it plays an important role in aging. It can be measured simply using small numbers of biomarkers. Additionally, there are indications of the importance during aging of
emergent physiological processes
, functional processes that cannot be easily understood through clear metabolic pathways, but can nonetheless be precisely quantified and studied. The overall role of such complex systems dynamics in aging remains an important open question, and to understand it future studies will need to distinguish and integrate related aspects of aging research, including multi-factorial theories of aging, systems biology, bioinformatics, network approaches, robustness, and loss of complexity.
The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger ...neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.
Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related ...pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations.
Mechanisms maintaining honesty of sexual signals are far from resolved, limiting our understanding of sexual selection and potential important parts of physiology. Carotenoid pigmented visual signals ...are among the most extensively studied sexual displays, but evidence regarding hypotheses on how carotenoids ensure signal honesty is mixed. Using a phylogenetically controlled meta-analysis of 357 effect sizes across 88 different species of birds, we tested two prominent hypotheses in the field: that carotenoid-dependent coloration signals i) immunocompetence and/or ii) oxidative stress state. Separate meta-analyses were performed for the relationships of trait coloration and circulating carotenoid level with different measures of immunocompetence and oxidative stress state. For immunocompetence we find that carotenoid levels (r = 0.20) and trait color intensity (r = 0.17) are significantly positively related to PHA response. Additionally we find that carotenoids are significantly positively related to antioxidant capacity (r = 0.10), but not significantly related to oxidative damage (r = -0.02). Thus our analyses provide support for both hypotheses, in that at least for some aspects of immunity and oxidative stress state the predicted correlations were found. Furthermore, we tested for differences in effect size between experimental and observational studies; a larger effect in observational studies would indicate that co-variation might not be causal. However, we detected no significant difference, suggesting that the relationships we found are causal. The overall effect sizes we report are modest and we discuss potential factors contributing to this, including differences between species. We suggest complementary mechanisms maintaining honesty rather than the involvement of carotenoids in immune function and oxidative stress and suggest experiments on how to test these.
Summary Background National malaria death rates are difficult to assess because reliably diagnosed malaria is likely to be cured, and deaths in the community from undiagnosed malaria could be ...misattributed in retrospective enquiries to other febrile causes of death, or vice-versa. We aimed to estimate plausible ranges of malaria mortality in India, the most populous country where the disease remains common. Methods Full-time non-medical field workers interviewed families or other respondents about each of 122 000 deaths during 2001–03 in 6671 randomly selected areas of India, obtaining a half-page narrative plus answers to specific questions about the severity and course of any fevers. Each field report was sent to two of 130 trained physicians, who independently coded underlying causes, with discrepancies resolved either via anonymous reconciliation or adjudication. Findings Of all coded deaths at ages 1 month to 70 years, 2681 (3·6%) of 75 342 were attributed to malaria. Of these, 2419 (90%) were in rural areas and 2311 (86%) were not in any health-care facility. Death rates attributed to malaria correlated geographically with local malaria transmission ratesderived independently from the Indian malaria control programme. The adjudicated results show 205 000 malaria deaths per year in India before age 70 years (55 000 in early childhood, 30 000 at ages 5–14 years, 120 000 at ages 15–69 years); 1·8% cumulative probability of death from malaria before age 70 years. Plausible lower and upper bounds (on the basis of only the initial coding) were 125 000–277 000. Malaria accounted for a substantial minority of about 1·3 million unattended rural fever deaths attributed to infectious diseases in people younger than 70 years. Interpretation Despite uncertainty as to which unattended febrile deaths are from malaria, even the lower bound greatly exceeds the WHO estimate of only 15 000 malaria deaths per year in India (5000 early childhood, 10 000 thereafter). This low estimate should be reconsidered, as should the low WHO estimate of adult malaria deaths worldwide. Funding US National Institutes of Health, Canadian Institute of Health Research, Li Ka Shing Knowledge Institute.
Many studies of aging examine biomarkers one at a time, but complex systems theory and network theory suggest that interpretations of individual markers may be context-dependent. Here, we attempted ...to detect underlying processes governing the levels of many biomarkers simultaneously by applying principal components analysis to 43 common clinical biomarkers measured longitudinally in 3694 humans from three longitudinal cohort studies on two continents (Women's Health and Aging I & II, InCHIANTI, and the Baltimore Longitudinal Study on Aging). The first axis was associated with anemia, inflammation, and low levels of calcium and albumin. The axis structure was precisely reproduced in all three populations and in all demographic sub-populations (by sex, race, etc.); we call the process represented by the axis "integrated albunemia." Integrated albunemia increases and accelerates with age in all populations, and predicts mortality and frailty--but not chronic disease--even after controlling for age. This suggests a role in the aging process, though causality is not yet clear. Integrated albunemia behaves more stably across populations than its component biomarkers, and thus appears to represent a higher-order physiological process emerging from the structure of underlying regulatory networks. If this is correct, detection of this process has substantial implications for physiological organization more generally.
Abstract
The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such “geroprotective” therapies in ...humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972–1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71–cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.
What if there’s no such thing as “aging”? Cohen, Alan A.; Legault, Véronique; Fülöp, Tamàs
Mechanisms of ageing and development,
December 2020, 2020-12-00, 20201201, Letnik:
192
Journal Article
Recenzirano
Odprti dostop
•Our mental categories tend to correspond to our linguistic categories.•We argue there is no biological phenomenon that corresponds to the word “aging”.•We show how the concept of “aging” misleads us ...from asking the right questions.•We lay out a path for aging research without the concept of “aging” itself.•We advocate gradual abandonment of the word “aging” in scientific contexts.
Are diseases caused by aging? What are the mechanisms of aging? Do all species age? These hotly debated questions revolve around a unitary definition of aging. Because we use the word “aging” so frequently, both colloquially and scientifically, we rarely pause to consider whether this word maps to an underlying biological phenomenon, or whether it is simply a grab-bag of diverse phenomena linked more by our mental associations than by any underlying biology. Here, we consider how the presence of the colloquial word “aging” generates a cognitive bias towards supposing there is a unitary biological phenomenon. We ask what kind of evidence would support or refute that idea, and subsequently show clear evidence at multiple levels that aging is not a unitary phenomenon. In particular, the known aging pathways lead to heterogeneous outputs, not a single coordinated phenomenon. From levels ranging from cellular/molecular to clinical to demographic to evolutionary, we show how the supposition that aging is a unitary phenomenon can mislead and distract us from asking the best questions. For major sub-disciplines of aging biology, we show how going beyond the notion of unitary aging can hone the paradigm and help advance the pace of discovery.