Complex adaptive systems, aging and longevity.

Mortality and reproduction are intimately entwined in the study of aging and longevity. I apply the modern theory of complex adaptive systems (nonlinear, stochastic, dynamic methods) to questions of aging and longevity. I begin by highlighting major questions that must be answered in order to obtain a deeper understanding of aging. These are: (i) What should (in an evolutionary sense) mortality trajectories look like? (ii) Why does caloric restriction slow aging? (iii) Why does reproduction cause delayed mortality? (iv) Why does compensatory growth cause delayed mortality? I show how dynamic state variable models based on stochastic dynamic programming (Clark & Mangel, 2000) can be used to embed genetic theories of senescence (either mutation accumulation or antagonistic pleiotropy) in the somatic environment, as George Williams called for in 1957, and how they make the disposable soma theory of aging operational. Such models will allow unification of genetic and phenotypic theories of aging.     

Evolvability,population benefit,and the evolution of programmed aging in mammals

Programmed aging theories contend that evolved biological mechanisms purposely limit internally determined lifespans in mammals and are ultimately responsible for most instances of highly age-related diseases and conditions. Until recently, the existence of programmed aging mechanisms was considered theoretically impossible because it directly conflicted with Darwin’s survival-of-the-fittest evolutionary mechanics concept as widely taught and generally understood. However, subsequent discoveries, especially in genetics, have exposed issues with some details of Darwin’s theory that affect the mechanics of the evolution process and strongly suggest that programmed aging mechanisms in humans and other mammals can and did evolve, and more generally, that a trait that benefits a population can evolve even if, like senescence, it is adverse to individual members of the population. Evolvability theories contend that organisms can possess evolved design characteristics (traits) that affect their ability to evolve, and further, that a trait that increases a population’s ability to evolve (increases evolvability) can be acquired and retained even if it is adverse in traditional individual fitness terms. Programmed aging theories based on evolvability contend that internally limiting lifespan in a species-specific manner creates an evolvability advantage that results in the evolution and retention of senescence. This issue is critical to medical research because the different theories lead to dramatically different concepts regarding the nature of biological mechanisms behind highly age-related diseases and conditions.     

Evolution of aging theories: Why modern programmed aging concepts are transforming medical research

Programmed aging refers to the idea that senescence in humans and other organisms is purposely caused by evolved biological mechanisms to obtain an evolutionary advantage. Until recently, programmed aging was considered theoretically impossible because of the mechanics of the evolution process, and medical research was based on the idea that aging was not programmed. Theorists struggled for more than a century in efforts to develop non-programmed theories that fit observations, without obtaining a consensus supporting any non-programmed theory. Empirical evidence of programmed lifespan limitations continued to accumulate. More recently, developments, especially in our understanding of biological inheritance, have exposed major issues and complexities regarding the process of evolution, some of which explicitly enable programmed aging of mammals. Consequently, science-based opposition to programmed aging has dramatically declined. This progression has major implications for medical research, because the theories suggest that very different biological mechanisms are ultimately responsible for highly age-related diseases that now represent most research efforts and health costs. Most particularly, programmed theories suggest that aging per se is a treatable condition and suggest a second path toward treating and preventing age-related diseases that can be exploited in addition to the traditional disease-specific approaches. The theories also make predictions regarding the nature of biological aging mechanisms and therefore suggest research directions. This article discusses developments of evolutionary mechanics, the consequent programmed aging theories, and logical inferences concerning biological aging mechanisms. It concludes that major medical research organizations cannot afford to ignore programmed aging concepts in assigning research resources and directions.     

The role of the MEK/ERK pathway in regulation of HDACI-induced senescence of transformed rat embryo fibroblasts

A key regulator of cellular senescence, mTORC1 complex, is a target of many signaling cascades, including Ras/Raf/MEK/ERK cascade. In this paper, we investigated the role of the MEK/ERK branch of this cascade in the process of cellular senescence induced by sodium butyrate (NaBut), a histone deacetylase inhibitor (HDACI), in transformed rat-embryo fibroblasts. Suppression of MEK/ERK activity by inhibitor PD0325901 did not prevent activation of mTORC1 complex induced by NaBut treatment. Inhibition of MEK/ERK increased mTORC1 activity and activated mTORC2 complex. Activation of mTOR-containing complexes was accompanied by reorganization of the actin cytoskeleton (formation of actin stress fibers) and the appearance of cellular senescence markers. In contrast to NaBut-induced senescence, no protein accumulation was observed, probably due to increased activity of the degradation processes. Furthermore, senescence induction under suppression of MEK/ERK drastically decreased the cell viability, Thus, NaBut-induced senescence upon suppressed activity of the MEK/ERK branch of MAP kinase cascade has a more pronounced tumor-suppressing effect that is manifested by activation of both mTOR complexes, reorganization of the actin cytoskeleton and protein degradation.     

The exotic and the mundane

The HIV/AIDS epidemic in Haiti has often been referred to as a “mystery,” and “striking similarities” between patterns of disease in Haiti and in sub-Saharan Africa are often underlined. The occurrence of AIDS in Haitians has also led to the postulation of a number of theories positing a Haitian origin for AIDS and linking the syndrome in Haitians to voodoo. A review of the epidemiological data gathered and published in the early years of the pandemic suggests that these “exotic” theories are not necessary to explain the Haitian epidemic, which is clearly linked not to Africa but to the United States. Patterns of risk identified among many of the first Haitians with AIDS are similar to risk factors identified in North America and Europe (same-sex contact with an HIV-infected individual and blood transfusion). The Haitian epidemicsubsequently came to resemble patterns seen in sub-Saharan Africa, where AIDS is predominantly a heterosexually transmitted disease. Similarly shifting patterns are described for several other Caribbean nations, underlining the importance of a historical analysis of the Caribbean pandemic as well as the necessity to link analysis of local epidemiology of AIDS/HIV to larger considerations of political economy.     

A Philosophical Evaluation of Adaptationism as a Heuristic Strategy

Adaptationism has prompted many a debate in philosophy of biology but the focus is usually on empirical and explanatory issues rather than methodological adaptationism (MA). Likewise, the context of evolutionary biology has provided the grounding for most discussions of the heuristic role of adaptationism. This paper extends the debate by drawing on case studies from physiology and systems biology to discuss the productive and problematic aspects of adaptationism in functional as well as evolutionary studies at different levels of biological organization. Gould and Lewontin’s Spandrels-paper famously criticized adaptationist methodology for implying a risk of generating ‘blind spots’ with respect to non-selective effects on evolution. Some have claimed that this bias can be accommodated through the testing of evolutionary hypotheses. Although this is an important aspect of overcoming the pitfalls of adaptationism, I argue that the issue of methodological biases is broader than the question of testability. I demonstrate the productivity of adaptationist heuristics but also discuss the deeper problematic aspects associated with the imperialistic tendencies of the strong account of MA.     

The logical structure of evolutionary explanation and prediction: Darwinism’s fundamental schema

We present a logically detailed case-study of Darwinian evolutionary explanation. Special features of Darwin’s explanatory schema made it an unusual theoretical breakthrough, from the point of view of the philosophy of science. The schema employs no theoretical terms, and puts forward no theoretical hypotheses. Instead, it uses three observational generalizations—Variability, Heritability and Differential Reproduction—along with an innocuous assumption of Causal Efficacy, to derive Adaptive Evolution as a necessary consequence. Adaptive Evolution in turn, with one assumption of scale (‘Deep Time’), implies the observational generalization of Adaptation. It is a fascinating methodological task to regiment the premises and make the reasoning both rigorous and clear. Doing so reveals how surprisingly small an amount of mathematics is needed in order to carry out the argument. The investigation also reveals the crucial role played by heritability, and how heritability itself admits of Darwinian explanation.     

Integrating evolutionary and molecular genetics of aging

Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.     

Comparison of N-Methyl-d-aspartate Receptor Subunit 1 and 4-Hydroxynonenal in the Hippocampus of Natural and Chemical-Induced Aging Accelerated Mice

In this study, we compared N-methyl-d-aspartate receptor type 1 (NMDAR1) and 4-hydroxynonenal (4-HNE) in the hippocampus of d-galactose (d-gal)-induced and naturally aging models of mice. These markers represent general phenotypes in aging, and they allowed us to examine the possibility of d-gal as a chemical model agent for aging. We observed an age-dependent reduction of NMDAR1 and an increase in 4-HNE in the dentate gyrus, CA1, and CA3 regions of the hippocampus via immunohistochemistry and western blot analyses. In the d-gal-induced chemical aging model, we observed similar changes in NMDAR1 and 4-HNE although the degree of reduction/increase in NMDAR1/4-HNE was not as severe as that in the naturally aged mice. These results suggest that the d-gal-induced aging model is comparable to naturally aged mice and may be useful for studies of the aging hippocampus.     

Analyses of the Similarity and Difference of Global Gene Expression Profiles in Cortex Regions of Three Neurodegenerative Diseases: Sporadic Creutzfeldt-Jakob Disease (sCJD), Fatal Familial Insomnia (FFI), and Alzheimer’s Disease (AD)

Neurodegenerative disease is a general designation for the disorders that are progressive loss of structure or function and final death of neurons, including Alzheimer’s, Parkinson’s, Huntington’s, prion diseases, etc. In this study, we comparatively analyzed 21 individual microarray data sets of the cortex tissues from 11 sporadic Creutzfeldt-Jakob disease (sCJD), 3 fatal familial insomnia (FFI), 3 Alzheimer’s disease (AD), and 4 normal controls. After normalization, a collection of 730 differently expressed sets (DESets) were obtained by comparison of the data of three diseases with their original controls. Principal component analysis (PCA) showed a background-related distribution within the groups of FFI, AD, and normal control, but two apparently different subgroups within the group of sCJD were observed. Review of the clinical materials of 11 sCJD patients identified the difference in brain PrP^Sc deposits between two subgroups. Hierarchical cluster analysis illustrated the relatively independent clusters of normal controls, FFIs, six sCJD cases (subgroup 1) with more PrP^Sc deposits, respectively, while an overlapped cluster of five cases of sCJD2 (subgroup 2) with less PrP^Sc deposits and AD patients. Despite of the presence of special gene expressions, many common features were found among those neurodegenerative diseases. The most commonly changed biological processes (BPs) were signal transduction, synaptic transmission, and neuropeptide signaling pathway. The most commonly changed pathways were MAPK signaling pathway, Parkinson’s disease, and oxidative phosphorylation. Our data here provide the similarity and difference in global gene expressions among the patients with sCJD, FFI, and AD, which may help to understand the common mechanism of neurodegenerative diseases.     

Peroxiredoxins as multifunctional enzymes

Peroxiredoxins are an evolutionary ancient widespread group of selenium-independent peroxidases. Peroxiredoxins protect cells from various peroxides, play an important role in maintaining redox homeostasis, and are additionally involved in transmitting extracellular and intracellular signals. The review considers peroxiredoxins from different kingdoms of living organisms and discusses the recent data on their structure, function, and the expression regulation of their genes.     

Methodological problems in evolutionary biology I. Testability and tautologies

The impact of philosophy of science on biology is slight. Evolutionary biology, however, is nowadays an exception. The status of the neo-Darwinian (synthetic) theory of evolution is seriously challenged from a methodological perspective. However, the methodology used in the relevant discussions is plainly defective. A correct application of methodology to evolutionary theory leads to the following conclusions. (a) The theory of natural selection (the core of neo-Darwinism) is unfalsifiable in a strict sense of the term. This, however, does not militate against the theory, because no scientific theory whatever is testable in this way. Under a more liberal testability criterion, the theory is surely testable. None the less, certain (not all) research programs may tend to make the theory untestable in practice. (b) It has often been argued that the tautologous character of the principle of natural selection, allegedly the focus of evolutionary theory, makes the theory untestable through circular reasoning. Actually, the principle is only a tautology if ‘fitness’ is wrongly defined in terms of actual survival. But even then circular reasoning need not ensue. (c) Evolutionary principles do not permit, without additional information, the derivation of statements about evolutionary events concerning particular species or populations. If this were a reason to criticize the theory (as has been argued in the literature), any other scientific theory would be inadequate by the same token.     

Negative Purifying Selection Drives Prion and Doppel Protein Evolution

The prion protein (PrP) when misfolded into the pathogenic conformer PrP^Sc is the major causative agent of several lethal transmissible spongiform encephalopathies in mammals. Studies of evolutionary pressure on the corresponding gene using different datasets have yielded conflicting results. In addition, putative PrP or PrP interacting partners with strong similarity to PrP such as the doppel protein have not been examined to determine if the same evolutionary mechanisms apply to prion paralogs or if there are coselected sites that might indicate how and where the proteins interact. We examined several taxonomic groups that contain model organisms of prion diseases focusing on primates, bovids, and an expanded dataset of rodents for selection pressure on the prion gene (PRNP) and doppel gene (PRND) individually and for coevolving sites within. Overall, the results clearly indicate that both proteins are under strong selective constraints with relaxed selection on amino acid residues connecting α-helices 1 and 2.     

A comparative approach to the organization of vocal signals in noctural prosimians

Vocalizations and corresponding behavior patterns were recorded inGalago demidovii (Lorisidae), Microcebus murinus, andCheirogaleus medius (Cheirogaleidae). Physical characteristics of the calls were analyzed and calls correlated with their behavioral context. Based on these correlations an «advertisement» call can be identified in all three species. Interspecific comparison suggest that within the Prosimian suborder there are at least two different evolutionary pathways in the organization of this call and of the vocal repertoires in general. The Lorisid speciesG. demidovii conveys acoustic information mainly in pulsed calls, leading to an extreme amplitude-modulation. Individual characteristics are in temporal patterns of calls.C. medius andM. murinus, the Cheirogaleid species, use tonal calls and encode individual characteristics in frequency patterns. Despite the fundamental similarity in the call-structure of the two Cheirogaleid species different adaptations can be found to meet different ecological needs.     

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

The role of the mitochondria in disease, general health and aging has drawn much attention over the years. Several attempts have been made to describe how the numbers of mitochondria correlate with age, although with inconclusive results. In this study, the relative quantity of mitochondrial DNA compared to nuclear DNA, i.e. the mitochondrial DNA copy number, was measured by PCR technology and used as a proxy for the content of mitochondria copies. In 1,067 Danish twins and singletons (18–93 years of age), with the majority being elderly individuals, the estimated mean mitochondrial DNA copy number in peripheral blood cells was similar for those 18–48 years of age [mean relative mtDNA content: 61.0; 95 % CI (52.1; 69.9)], but declined by ?0.54 mtDNA 95 % CI (?0.63; ?0.45) every year for those older than approximately 50 years of age. However, the longitudinal, yearly decline within an individual was more than twice as steep as observed in the cross-sectional analysis [decline of mtDNA content: ?1.27; 95 % CI (?1.71; ?0.82)]. Subjects with low mitochondrial DNA copy number had poorer outcomes in terms of cognitive performance, physical strength, self-rated health, and higher all-cause mortality than subjects with high mitochondrial DNA copy number, also when age was controlled for. The copy number mortality association can contribute to the smaller decline in a cross-sectional sample of the population compared to the individual, longitudinal decline. This study suggests that high mitochondrial DNA copy number in blood is associated with better health and survival among elderly.     

Epigenetic Signature of Chronic Cerebral Hypoperfusion and Beneficial Effects of S-adenosylmethionine in Rats

Chronic cerebral hypoperfusion is associated with cognitive decline in aging and age-related neurodegenerative disease. Epigenetic mechanisms are involved in the maintenance of long-term hypoxia-adapted cellular phenotypes. In the present study, the epigenetic signatures such as DNA methylation and histone acetylation, as well as S-adenosylmethionine (SAM) cycle using chronic cerebral hypoperfusion rat model were explored. Chronic cerebral hypoxia-induced global DNA hypermethylation associated with the increase of DNA methyltransferase (DNMT) 3A as well as alteration of SAM cycle. Meanwhile, an enhanced level of global histone H4 acetylation accompanied with the upregulation of histone acetyltransferase, p300/CREB-binding protein (CBP), and the downregulation of histone deacetylases (HDACs), was also observed. SAM could improve spatial capacity through the upregulation of acetylcholine and brain-derived neurotrophic factor (BDNF) rather than alteration of DNA methylation levels. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic cerebral hypoxic conditions in a rat’s brain. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular responds with a potential role in memory deficits.     

Evolution and the sudden infant death syndrome (SIDS)

This paper extends the evolutionary and developmental research model for SIDS presented in previous articles (McKenna 1990a, 1990b). Data from variety of fields were used to show why we should expect human infants to be physiologically responsive in a beneficial way to parental contact, one form of which is parent-infant co-sleeping. It was suggested that on-going sensory exchanges (touch, movement, smell, temperature, etc.) between co-sleeping parent-infant pairs might diminish the chances of an infantile cardiac-respiratory crisis (such as those suspected to occur in some SIDS cases). In this article we review recent epidemiological data and sleep research findings on SIDS to show how they relate to evolutionary and cross-cultural perspectives. Results of a preliminary study of the co-sleeping behavior of mother-infant pairs indicate that, with respect to sleep, arousal, and respiratory patterns, co-sleeping mother-infant pairs affect each other in potentially important ways. We suggest specifically that co-sleeping may shorten periods of consolidated sleep among young infants by causing them to arouse more frequently. Moreover, we suggest that partner-induced arousals might help the infant to confront sleep crises more competently. In the long run, these arousals might prevent the premature emergence of prolonged (adultlike) sleep bouts from which some infants have difficulty arousing—especially during a breathing pause or apnea.