Asymmetric Stem Cell Division and Germline Immortality.

Germ cells are the only cell type that is capable of transmitting genetic information to the next generation, which has enabled the continuation of multicellular life for the last 1.5 billion years. Surprisingly little is known about the mechanisms supporting the germline's remarkable ability to continue in this eternal cycle, termed germline immortality. Even unicellular organisms age at a cellular level, demonstrating that cellular aging is inevitable. Extensive studies in yeast have established the framework of how asymmetric cell division and gametogenesis may contribute to the resetting of cellular age. This review examines the mechanisms of germline immortality-how germline cells reset the aging of cells-drawing a parallel between yeast and multicellular organisms.

rDNA magnification is a unique feature of germline stem cells.

Ribosomal DNA (rDNA) encodes ribosomal RNA and exists as tandem repeats of hundreds of copies in the eukaryotic genome to meet the high demand of ribosome biogenesis. Tandemly repeated DNA elements are inherently unstable; thus, mechanisms must exist to maintain rDNA copy number (CN), in particular in the germline that continues through generations. A phenomenon called rDNA magnification was discovered over 50 y ago in Drosophila as a process that recovers the rDNA CN on chromosomes that harbor minimal CN. Our recent studies indicated that rDNA magnification is the mechanism to maintain rDNA CN under physiological conditions to counteract spontaneous CN loss that occurs during aging. Our previous studies that explored the mechanism of rDNA magnification implied that asymmetric division of germline stem cells (GSCs) may be particularly suited to achieve rDNA magnification. However, it remains elusive whether GSCs are the unique cell type that undergoes rDNA magnification or differentiating germ cells are also capable of magnification. In this study, we provide empirical evidence that suggests that rDNA magnification operates uniquely in GSCs, but not in differentiating germ cells. We further provide computer simulation that suggests that rDNA magnification is only achievable through asymmetric GSC divisions. We propose that despite known plasticity and transcriptomic similarity between GSCs and differentiating germ cells, GSCs' unique ability to divide asymmetrically serves a critical role of maintaining rDNA CN through generations, supporting germline immortality.

ZSP-1 is a Z granule surface protein required for Z granule fluidity and germline immortality in Caenorhabditis elegans.

Germ granules are biomolecular condensates that form in germ cells of all/most animals, where they regulate mRNA expression to promote germ cell function and totipotency. In the adult Caenorhabditis elegans germ cell, these granules are composed of at least four distinct sub-compartments, one of which is the Z granule. To better understand the role of the Z granule in germ cell biology, we conducted a genetic screen for genes specifically required for Z granule assembly or morphology. Here, we show that zsp-1, which encodes a low-complexity/polyampholyte-domain protein, is required for Z granule homeostasis. ZSP-1 localizes to the outer surface of Z granules. In the absence of ZSP-1, Z granules swell to an abnormal size, fail to segregate with germline blastomeres during development, and lose their liquid-like character. Finally, ZSP-1 promotes piRNA- and siRNA-directed gene regulation and germline immortality. Our data suggest that Z granules coordinate small RNA-based gene regulation to promote germ cell function and that ZSP-1 helps/is need to maintain Z granule morphology and liquidity.

Non-senescent species are not immortal: Stress and decline in two planaria species.

Potential immortality is observed in several species (e.g. prickly pear cactus, hydra and flatworms) and is indicative of their negligible or even negative senescence rates. Unlike in senescent species, which experience reduced individual performance with age due to physiological degradation, species with negligible or negative senescence display mortality rates that remain constant or decline with age, respectively. These rates vary across taxa and are correlated with life history traits. Yet, the extent to which variable resource availability, a key driver of variation in life history traits, impacts species that show negligible or negative senescence is currently unknown. Here, we examine whether and how variation in the quantity, quality and feeding interval of resources impact population structure, population performance and life history trait trade-offs in two long-lived planaria that do not senesce: Schmidtea mediterranea and Dugesia tahitiensis. In a full factorial design, different combinations of resource quantity (reduced intake, standard intake and high intake) and quality (high and low quality) were provided in two different feeding intervals (7-day and 14-day intervals) for 19 weeks. We show that variability in resource availability, via decreases in quantity, quality and frequency of resources, does not diminish population viability in either species but does result in suboptimal conditions of stress in S. mediterranea. The high population viability we report can be attributed to two different mechanisms: increased reproduction or increased investment into maintenance at the expense of reproduction. Moreover, which mechanism was responsible for said high population viability was context-dependent and modulated by the specific life history strategy of the two planaria species. We show that suboptimal conditions can cause stress responses that have significant impacts on non-senescent species. The context-dependent response we observe suggests that species that do not senesce but are subject to suboptimal conditions of stress may ultimately exhibit declines in performance and ultimately die. A clearer understanding of the impact of suboptimal conditions of resource availability on non-senescent species is needed to determine the extent of stress experienced and ultimately whether a species can truly be immortal.

Some Considerations on a Patient's Sense of Immortality: Bringing a Human Dimension to the Process.

One of the most frequent, although widely understandable, reactions of people diagnosed with an incurable tumor is represented by incredulity, anger, and the denial of the impossibility of a definitive cure. Often, a picture of intense anxiety quickly takes over, overlapping the ever-growing collective hysteria of modern society, the result of a complex cultural mechanism in which technocracy often prevails over thought, introspection, and, in a broader sense, humanism. In this health drama, all actors often complain of formal inaccuracies while paying little attention to substantive ones. We argue that a more human emphatic patient-family-doctor relationship training to consider the undeniable progress of medicine and the fragility of all of us.

Synthesizing Methuselah: The Question of Artificial Agelessness.

As biological organisms, we age and, eventually, die. However, age's deteriorating effects may not be universal. Some theoretical entities, due to their synthetic composition, could exist independently from aging-artificial general intelligence (AGI). With adequate resource access, an AGI could theoretically be ageless and would be, in some sense, immortal. Yet, this need not be inevitable. Designers could imbue AGIs with artificial mortality via an internal shut-off point. The question, though, is, should they? Should researchers curtail an AGI's potentially endless lifespan by deliberately making it mortal? It is this question that this article explores. First, it considers what type of AGI is under discussion before outlining how such beings could be ageless. Then, after clarifying the type of immortality under discussion and arguing that imbuing an AGI with synthetic aging would be person-affecting, the article explores four core conundrums: (i) deliberately causing a morally significant being's death; (ii) immortality's associated harms; (iii) concerns about immortality's unequal assignment; and (iv) the danger of immortal AGI overlords. The article concludes that while prudence requires we create an aging AGI, in the face of the material harm such an action would constitute, this is an insufficient reason to justify doing so.

Christianity.

The Christian faith is founded on the principle that human life is sacred, a gift from God, the Heavenly Father. Christians live to love and glorify God. Throughout life, they witness a myriad of life events covering the spectrum from euphoric highs to devastating lows. Be it joy or sorrow, faith in God, having been established through a personal relationship with His Son, Jesus Christ of Nazareth as Savior and Lord, sustains and guides every step. The end of life is the closing earthly chapter, often shared with family members, a chaplain, parish pastor, or another spiritual care provider assisting the dying Christian with compassionate and significant conversations. It is a time to complete preparations for the final journey every Christian takes from this life into the glorious eternal life prepared in heaven with God the Heavenly Father, Jesus Christ the Savior, family, and friends who have gone before. This chapter examines various rituals and practices of the Christian faith observed during the end of life, legacy or life review, funeral practices, burial rituals following death, beliefs about the afterlife that inspire and inform the great hopes of Christian living, and bereavement support for grieving.

Protection of germline immortality by the soma via a secreted endoribonuclease.

In sexually reproducing organisms maintenance of germ stem cell immortality is fundamental for transmitting genetic material to future generations. While previous research has mainly considered intrinsic regulatory mechanisms in the germline, our recent study has found a direct contribution of somatic cells in preserving germline immortality via the somatically expressed endoribonuclease ENDU-2 in Caenorhabditis elegans. We have identified ENDU-2 as a secreted protein that can be taken up by the germline. Here, we discuss how ENDU-2 might uncouple its RNA-binding and RNA-cleavage activities to control gene expression via either an endoribonuclease dependent or an independent way. We also speculate on a possible functional conservation of its mammalian homologs in mediating cell-cell communication as well as its potential significance in understanding human pathogenesis such as cancer development.

The epistemologies of research on the survival of consciousness after death in the golden era of the Society for Psychical Research (1882-1930).

The Society for Psychical Research (SPR) of London was founded in 1882 with the purpose of investigating psychical phenomena, especially the theme of survival, with scientific rigour. Despite the recognized importance of the SPR for dynamic psychiatry in the nineteenth and twentieth centuries, there are few studies of its epistemological contributions to the theme of survival and its implications to science. In order to fill this gap, we have consulted the main journals of the SPR in its golden period, and highlight the epistemologies of Sidgwick, Myers, James, Podmore, Schiller, Lodge and Richet. We conclude that the authors, whether for or against survival, argued in defence of an expanded science, and looked forward to understanding the complexity of human experience.

Association of Ageism With Death Anxiety, Self-Esteem, Interpersonal Reactivity, and Symbolic Immortality Among Nurses.

According toterror management theory (TMT), older adults may often be a reminder of death for younger adults. Therefore, dealing with older adults may be associated with increased levels of death anxiety and decreased levels of self-esteem, interpersonal reactivity, and symbolic immortality, leading younger adults to develop ageist attitudes and behaviors in defense. However, to date, these associations have not been empirically examined, especially among nurses. Self-report questionnaires were used on a sample of 163 nurses to explore the issue of ageism among nurses from the TMT perspective. The results indicated that, after controlling for sociodemographic variables, high levels of death anxiety and low levels of self-esteem, interpersonal reactivity, and symbolic immortality were associated with increased levels of ageism among nurses. Thus, the current study uses TMT to explain ageism among nurses, and the study findings may contribute to the development of psychological interventions aimed at reducing nurses' ageism.

Head Transplantation and Immortality: When Is Life Worth Living Forever?

Head transplantation fits within the broader conceptual space occupied by transhumanists and others who seek to extend the lives of human beings indefinitely. It is reasonable to reflect on whether, under what circumstances, and in what ways human immortality would be good. In this paper, I disambiguate the ways in which immortality might be considered a human good and then argue that immortality is neither necessary nor sufficient condition for objective meaning in life. I also argue that mortality is not a necessary condition for objective meaning in life.

Life Extension and Overpopulation: Demography, Morals, and the Malthusian Objection.

One of the main objections to life extension is that life extension will cause severe overpopulation. This objection presents both moral and demographic issues. To explore the demographic issue, we present an updated and improved version of the formula in chapter six of New Methuselahs for projecting the demographic impact of life extension. The new version includes additional demographical factors such as non-aging related causes of death. According to projections generated with this revised formula, moderate life extension (a life expectancy of 120 years) will not significantly increase population at the fertility rates current in the developed world, but radical life expectancy (halting aging completely, leading to an average life expectancy of 1000 years) can lead to severe overpopulation even at very low fertility rates. This formula also enables us to ascertain what fertility rate and birth spacing will prevent life extension from causing severe overpopulation. The moral issues arise if radical life extension causes overpopulation severe enough to outweigh the benefits it brings. New Methuselahs proposed a reproductive policy for avoiding severe overpopulation by limiting reproduction for those who use life extension. We then consider a moral objection to this policy that was not discussed in New Methuselahs: it is not likely that society will succeed in imposing limits to reproduction, therefore, it is likely that radical life extension is morally wrong. We respond to this objection and defend our response against two further objections.

Quo Vadis, Dottore? Religious, Philosophical and Medical Perspectives on the Quest for Immortality.

In the daily practice of medicine, health care providers oftentimes confront the dilemma of offering 'maximum care' based on available technologies and advances versus ethical concerns about futility. Regardless of cultural backgrounds and differences, most human beings aspire to an illness-free life, or better yet, a life lived with utmost quality and longevity. On account on ongoing advances in science and technology, the possibility of achieving "immortality" (a term used as a metaphor for an extremely long and disease-free life) is increasingly perceived as a realistic goal, which is aggressively pursued by some of the world's wealthiest individuals and corporations. However, this quest is not taking place in a philosophical or religious vacuum, which is why we attempt to evaluate the current state of knowledge on religious beliefs revolving around immortality and their alignments with today's medical advancements. The literature searches were performed using relevant databases including JSTOR and PubMed, as well as primary religious sources. Most religions present longevity as a blessing and believe in some sort of immortality, afterlife or reincarnation for the immortal soul. The quest for immortality beyond life in a "body of death" remains consistent with access to medical care and the legitimate possibility of achieving longevity-as long as certain ethical and religious parameters are preserved.

"Life Is So Good": Centenarians' Autobiographies Between the Promise of Immortality and the Specter of Death.

When we are trying to come to terms with death and dying, or the loss of a loved one, cultural practices can fulfill important functions. Literature, music, and the arts can help us cope with loss by expressing our emotions in a way which seems to be universal. This paper investigates the role of co-written centenarians' autobiographies in this context. It focuses specifically on autobiographies by African American centenarians and white co-authors. The article investigates the dialogue between the centenarian and the co-author as a ritual for coming to terms with the co-author's fear of mortality. It argues that for a white readership that defines itself as secular, the black centenarian - deeply religious himself - can serve as a surrogate and a role model. Just as he assures his middle-aged, white co-author that death is not to be feared, his autobiography may offer a secular readership a model for dying.

Coloniality, clonality, and modularity in animals: The elephant in the room.

Nearly half of the animal phyla contain species that propagate asexually via agametic reproduction, often forming colonies of genetically identical modules, that is, ramets, zooids, or polyps. Clonal reproduction, colony formation, and modular organization have important consequences for many aspects of organismal biology. Theories in ecology, evolution, and development are often based on unitary and, mainly, strictly sexually reproducing organisms, and though colonial animals dominate many marine ecosystems and habitats, recognized concepts for the study of clonal species are often lacking. In this review, we present an overview of the study of colonial and clonal animals, from the historic interests in this subject to modern research in a range of topics, including immunology, stem cell biology, aging, biogeography, and ecology. We attempt to portray the fundamental questions lying behind the biology of colonial animals, focusing on how colonial animals challenge several dogmas in biology as well as the remaining puzzles still to be answered, of which there are many.

Between hoping to die and longing to live longer.

Drawing on Ezekiel Emanuel's controversial piece 'Why I hope to die at 75,' I distinguish two types of concern in ethical debates about extending the human lifespan. The first focusses on the value of living longer from prudential and social perspectives. The second type of concern, which has received less attention, focusses on the value of aiming for longer life. This distinction, which is overlooked in the ethical literature on life extension, is significant because there are features of human psychology and the structure of a life that should give pause when considering how long one should aim to live, but which do not neatly coincide with considerations about how valuable additional life is likely to be. I argue that, while Emanuel's case for hoping to die at 75 is unconvincing, he nonetheless provides weak pro tanto considerations in favour of taking a moderate life span as a prudential aim around which to base at least some significant life plans.

Symbols and Dynamics of Social Meanings: Lessons From Residential Grave Spaces Among the Ekiti Yoruba of Southwest Nigeria.

Grave spaces within Yoruba (Nigeria) societies are not just ordinary symbols, and they constitute "other place" used to meet individuals' physical and social needs. This study examined how residential grave spaces within Yoruba social structure are used by them in meeting their day-to-day needs. Drawing from symbolic interactionism theory, and data gathered from Ekiti-Yoruba culture, this study investigates how community members define and utilize the place of graves from traditional to modern society in meeting their needs. Findings revealed that during the precolonial society, grave spaces served religious and endearment purposes. While still retaining these functions in modern era, the functions have increased to security, protections, and power play due to the hurdles posed by modernity. The article concluded that the practice may continue in spite of its opposition by policy makers and orthodox faiths.

Crossroads of telomere biology and anticancer drug discovery.

The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.

Telomere length: how the length makes a difference.

Telomerase is perceived as an immortality enzyme that might provide longevity to cells and whole organisms. Importantly, it is generally inactive in most somatic cells of healthy, adult men. Consequently, its substrates, i.e. telomeres, get shorter in most human cells with time. Noteworthy, cell life limitation due to telomere attrition during cell divisions, may not be as bad as it looks since longer cell life means longer exposition to harmful factors. Consequently, telomere length (attrition rate) becomes a factor that is responsible for inducing the signaling that leads to the elimination of cells that lived long enough to acquire severe damage. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile that reflects sex, etc.) might become a useful marker of aging and exposition to stress. Thus in the current paper, we review the factors that affect telomere length in human cells focusing on sex that all together with different environmental and hormonal regulations as well as parental aspect affect telomere attrition rate. We also raise some limitations in the assessment of telomere length that hinders a trustworthy meta-analysis that might lead to acknowledgment of the real value of this parameter.

Genomic research delivering on promises: From rejuvenation to vaccines and pharmacogenetics.

WHAT IS KNOWN AND OBJECTIVE: There has been astounding progress made in the treatment of disease over recent years. This progress is particularly marked in cell therapy and in the personalization of therapy based on genetic insight, an approach known as genomic medicine. Our objective is to comment on the progress made in cell and genomic medicine against an historical backcloth of the search for rejuvenation. COMMENT: In 1741, close to seven decades after Antoine van Leeuwenhoek first saw his microscopic animalcules, Abraham Trembley, a tutor in Leiden, reported on an organism that could regenerate itself. The strange organism was thought to hold the secret of life. If it does, we have yet to prise the secret out. However, the ensuing study of cell programming and induced stem cells has shed considerable light on cellular development and provided new insights on the rejuvenative capacity of organisms. Inventive scientists have provided a deeper understanding of cell replication and, from this, developed new medicines for an increasing range of diseases. Targeted therapies, oligonucleotide therapy, therapeutic monoclonal antibodies and pharmacogenetics are all new therapeutic areas originating from the improved insights. More will surely follow. WHAT IS NEW AND CONCLUSION: Immortality is for the gods, but man's search for its elusive secrets, perhaps as old as man himself, will continue. Huge leaps have been made, and effective medicines have been developed from our improved insights into the mechanism of life. However, only the foolish will predict how far this new knowledge will lead us, and more particularly, at what speed new therapies will follow.