• Fight Aging! Newsletter May 21st 2018 (1/3)

    From More Granularity@21:1/5 to All on Sun May 20 15:24:12 2018

    Fight Aging! Newsletter
    May 21st 2018

    Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well
    as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising
    initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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    Arguing for Mitochondrial ROS to Cause Stochastic Nuclear DNA Damage that then Causes Cellular Senescence
    Reduced C/EBPβ-LIP Expression Modestly Slows Aging in Mice
    Considering Mitochondria and Neurodegeneration
    Is Lipid Level or Inflammation the Critical Factor for Cardiovascular Disease Risk?
    The Many Possible Influences of the Nucleolus in Aging
    Unexpectedly Better Results Cause Phase III Trial Failure for Gensight Increased Mitochondrial DNA Copy Number Slows Vascular Aging in Mice
    Improved Approaches to Messing with Metabolism Will Use Gene Therapies
    An Interview with Reason at the Life Extension Advocacy Foundation
    A View of Aging Centered Around Mutation and Senescence
    XPO1 as a Novel Target for Therapies to Enhance Autophagy
    Is the Architecture of the Nuclear Envelope Fundamental to the Evolution of Aging?
    Alcor Receives 5 Million Donation
    A Review of Growth Hormone in Aging
    The Damage Done by a Lack of Exercise, and Digging Yourself Out of the Hole Arguing for Mitochondrial ROS to Cause Stochastic Nuclear DNA Damage that then Causes Cellular Senescence

    The open access paper I'll point out today ties together a number of common themes in aging research. The authors propose that mitochondrial production of reactive oxygen species (ROS) is a significant cause of stochastic nuclear DNA damage, which in
    turn is a significant cause of cellular senescence. Those issues can then also disrupt mitochondrial function to increase ROS production, forming a feedback loop. In this view of the driving processes of aging, mitochondria are largely at fault for
    anything that can be pinned to rising levels of random mutations in nuclear DNA: cancer risk, cellular senescence, generally increased levels of cellular malfunction, and so forth.

    An important caution regarding this paper is that the researchers used mice with a DNA repair deficiency in order to assemble their data. Such animals exhibit the appearance of accelerated aging, but it isn't in fact accelerated aging. It is usually an
    excess of cellular damage that isn't all that relevant in normal aging - any sort of global dysfunction in cells will tend to share high level similarities with aging, even if the damage is different. When it is significantly different, however, you
    usually can't learn much from it. So whether or not work in such mice is in fact useful in understanding normal aging depends very strongly on the low-level biochemical details in question. That can be hard to judge for those of us who are not life

    The approach to the problem taken here sounds basically sensible as it is described below, but it nonetheless calls out for some form of confirming study in normal mice in order to rule out any peculiarity of DNA repair deficiency. One possibility would
    be to take one of the existing mitochondrially targeted antioxidant compounds and design a study that specifically evaluates reduced nuclear DNA mutation and reduced cellular senescence burden as a result of administration. Researchers have already run
    numerous studies in mice with these compounds, and some of that existing data might be helpful from this point of view. I note, however, that those studies didn't produce very large gains in life span where those gains were measured, which should perhaps
    temper our enthusiasm for this whole line of thought.

    Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance, and aging

    Cellular senescence was recently established to play a causal role in aging and many age-related diseases. Senescence is a programmed cell fate characterized by growth arrest, a metabolic shift, resistance to apoptosis and often a secretory phenotype.
    The senescent cell burden increases with age in virtually all vertebrates. In replicating human cells, shortened telomeres drive senescence. It has become increasingly clear that non-replicating cells also undergo senescence. However, in non-dividing
    cells, which are the majority of cells in mammalian organisms, the cause of senescence is not clear.

    A variety of cellular stressors including genotoxic, proteotoxic, inflammatory, and oxidative have been implicated in driving senescence. However, senescence itself is associated with many of these cellular stressors, making it very difficult to decipher
    cause and effect. For example, DNA damaging agents definitively cause increased senescence (e.g. in cancer patients). Yet senescent cells are defined by persistent activation of the DNA damage response, increased expression of surrogate markers of DNA
    damage and are able to trigger genotoxic stress in neighboring cells. Therefore, in vivo, the importance of DNA damage as a driver of senescence and aging is debated.

    Even less is known about endogenous DNA damage as a potential driver of senescence and aging. The vast majority of evidence implicating DNA damage in senescence comes from experiments implementing very high doses of environmental genotoxins such as
    ionizing radiation or doxorubicin. Also of note, all genotoxins damage not only DNA, but also all cellular nucleophiles including phospholipids, proteins, and RNA. Thus, it remains unknown whether physiological levels of spontaneous DNA damage is
    sufficient to drive cellular senescence.

    A major source of endogenous DNA damage is reactive oxygen species (ROS) produced during mitochondrial-based aerobic metabolism. Some mitochondrial-derived ROS, such as H2O2, can diffuse throughout the cell, resulting in oxidative damage to lipids,
    proteins, RNA and DNA. Thus, mitochondrial dysfunction, which leads to an increase in ROS production, was proposed to be central to the aging process. However, this too remains controversial.

    To address these gaps in knowledge, we utilized a genetic approach to increase endogenous nuclear DNA damage in mice. ERCC1-XPF is an endonuclease complex required for nucleotide excision repair, interstrand crosslink repair and the repair of a subset of
    DNA double-strand breaks. Mutations that mediate reduced expression of this enzyme cause accelerated aging in humans and mice. Genetic depletion of DNA repair mechanisms does not increase the amount of damage incurred, it simply accelerates the pace at
    which damage triggers a demonstrable physiological impact, affording an opportunity to investigate the role of endogenous nuclear DNA damage in driving senescence.

    Here, we demonstrate that Ercc1-/Δ mice accumulate oxidative DNA damage and senescent cells more rapidly than age-matched wild-type (WT) controls, yet comparable to WT mice over two years of age. Surprisingly, we found that Ercc1-/Δ mice are also under
    increased oxidative stress. Increased ROS production and decreased antioxidant buffering capacity contributed to the oxidative stress, which was also observed in aged WT mice. Treatment of Ercc1-/Δ mice with a mitochondrial-targeted radical scavenger (
    XJB-5-131) was sufficient to suppress oxidative DNA damage, senescence, and age-related pathologies. These data demonstrate that damage of the nuclear genome arising spontaneously in vivo is sufficient to drive cellular senescence. Our data also
    demonstrate that endogenous DNA damage, as a primary insult, is able to trigger increased reactive oxygen species (ROS) and further oxidative damage in vivo.

    By definition, the primary insult in untreated Ercc1-/Δ mice is unrepaired endogenous DNA damage to the nuclear genome. Not surprisingly, the Ercc1-/Δ mice accumulate senescent cells more rapidly than WT mice. This formally demonstrates that
    physiologically-relevant types and levels of endogenous DNA damage are able to trigger the time-dependent accumulation of senescent cells. Chronic administration of XJB-5-131 significantly reduced both oxidative DNA damage and senescence. The reduced
    level of senescent cells corresponded to a reduction in age-related morbidity. The observation that suppressing oxidant production is sufficient to decreases senescence indicates that reactive species are required to ultimately cause or maintain
    senescence in response to genotoxic stress.

    Reduced C/EBPβ-LIP Expression Modestly Slows Aging in Mice https://www.fightaging.org/archives/2018/05/reduced-c-ebp%ce%b2-lip-expression-modestly-slows-aging-in-mice/

    There is an unbounded amount of research work that might be performed to investigate methods of modestly slowing aging in mice. Doing no more than exploring the surrounding biochemistry related to mTOR might be enough to occupy most of the researchers
    capable of this work for a decade. The open access paper I'll point out today is an example of the type: the authors picked one of the scores of proteins identified as having a closer relationship to mTOR and its biochemistry, and spent several person-
    years of time and funding learning something about its role.This type of project could easily be multiplied a hundredfold, across dozens of teams, and that would still capture only a fraction of the state space to be explored. Cells are complicated.

    The research community will explore all of that state space in the fullness of time. This activity isn't, however, a cost-effective path towards meaningful therapies that might address aging in humans. That isn't even the goal of this research, though it
    is a useful flag to wave from time to time when seeking funding. The primary goal is to map all of mammalian metabolism, to fully understand its operation - knowledge is the motivation of pure science, not application of knowledge. Whenever researchers
    state in public that human life extension is only a distant prospect, they are thinking in terms of the time taken to gather a fairly complete understanding of cellular metabolism, and then on top of that the time taken to build a new metabolism that
    functions more efficiently and ages less rapidly.

    This is why I am much in favor of the SENS rejuvenation research approach to aging. The strategy there is to keep the metabolism we have, the one we don't fully understand, but that nonetheless works well enough while we are young, and periodically
    repair the known forms of root cause damage that make it run awry to produce degenerative aging. This way of looking at the problem bypasses the need to fully understand cellular metabolism, and even bypasses the need to fully understand exactly how the
    root cause damage produces aging. Thus a much smaller set of challenges in this line of work relate to planning, building, and executing successful repair therapies, while disrupting cellular biochemistry as little as possible. Via this path, it is
    possible to talk about significantly turning back aging within our lifetimes.

    Mutant mice hold back the years

    Biologists have created mice that live longer and appear to age more slowly than ordinary mice. In previous work, researchers developed mice with a mutation that reduces the animals' production of a protein called C/EBPβ-LIP. This mutation conferred
    metabolic benefits similar to those achieved by limiting calorie intake, which is known to extend lifespan in some animals.

    The team's new experiments show that female mice with the mutation lived approximately 10% longer than ordinary mice, and were less susceptible to cancer. As females aged, those with the mutation gained less weight and maintained better overall motor
    skills. Both male and female mice with reduced C/EBPβ-LIP were more resistant to age-related changes in the immune and metabolic systems, compared with control animals.

    Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice

    Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced
    signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPβ-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-

    Here we describe that reduced C/EBPβ-LIP expression due to genetic ablation of the uORF delays the development of age-associated phenotypes in mice. Moreover, female mice engineered in this way display an extended lifespan. Since LIP levels increase
    upon aging in wild type mice, our data reveal an important role for C/EBPβ in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPβ-LIP may offer new possibilities to
    treat age-related diseases and to prolong healthspan.

    Considering Mitochondria and Neurodegeneration https://www.fightaging.org/archives/2018/05/considering-mitochondria-and-neurodegeneration/

    Since mitochondria seem to be the dominant theme this week, today I thought I'd point out a couple of recent open access papers that focus on the role of mitochondrial function (and dysfunction) in the neurodegeneration that accompanies aging. Every cell
    bears a swarm of mitochondria, the descendants of ancient symbiotic bacteria. Even though mitochondria long ago evolved into integrated cellular components, they still behave very much like bacteria in many ways. They multiply through division, and can
    fuse together and swap component parts, pieces of the molecular machinery necessary to their function. They also contain their own DNA, distinct from that of the cell nucleus.

    The primary role of mitochondria is to undertake the energetic process of packaging chemical energy store molecules to power cellular operations. This is of particularly importance to energy-hungry tissues such as the brain, and why mitochondrial
    dysfunction with advancing age is thought to be especially relevant to neurodegenerative conditions. The evidence for this is more clear or less clear depending on which condition is discussed. In Parkinson's disease, for example, it is very evident that
    mitochondrial function is central to the characteristic loss of specialized neurons that drives the condition. For Alzheimer's disease, on the other hand, it is a real challenge to talk about the degree to which the numerous involved mechanisms are more
    or less important than one another. There is a lot of conflicting evidence.

    The decline of mitochondrial function with age appears to have several distinct causes, not all of which are fully understood. Quality control mechanisms responsible for destroying errant and worn out mitochondria become less effective in later life.
    Some forms of mitochondrial DNA damage can produce mitochondria that are more resilient to quality control or more able to replicate than their peers, and they can take over cells to make them malfunction and cause harm. But aside from this, all
    mitochondria change profoundly in activity and structure in older individuals, and this may be a broad reaction to rising levels of molecular damage or other changes in signaling and cell behavior, above and beyond issues caused by failing quality

    Brain Mitochondria, Aging, and Parkinson's Disease

    High energy requirements tissues such as the brain are highly dependent on mitochondria. Mitochondria are intracellular organelles deriving and storing energy through the respiratory chain by oxidative phosphorylation. In a single neuron, hundreds to
    thousands of mitochondria are contained. Non-inherited mitochondrial DNA (mtDNA) mutations are called somatic mutations and appear over time. Mutated mtDNA replication is better when compared to wild-type mtDNA, which facilitates its clonal expansion.
    Once mutated mtDNA reaches at least 60%, the cell will have deficient respiration and will accumulate additional mtDNA mutations until cell death.

    Somatic mtDNA mutations are important in aging and disease such as Parkinson's disease (PD). PD results mostly from the loss of dopaminergic neurons in the substantia nigra (SN). SN dopaminergic neurons are lost in an age and mitochondrial dysfunction
    related way. When compared to other neurons, SN dopaminergic neurons have more mtDNA deletions, where the load of mtDNA mutations parallels the deficiency of the respiratory chain.

    Aging, at the cell level, is an increasingly incapacity to recycle organelles and macromolecules. Mitochondria DNA is very vulnerable. The aging process is tightly linked to mtDNA deletions and point mutations and to reactive oxygen species (ROS).
    Additionally, mtDNA deletions and point mutations accumulate over time. This leads to energetics impairment, increased ROS production, mtDNA lesions, and the decline of mitochondrial respiration.

    Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

    The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose
    utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded
    and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress.

    To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded and aggregated proteins. Their importance is
    exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (of expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurodegenerative
    diseases such as Alzheimer's, Parkinson's or even Huntington's diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones
    to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.

    Is Lipid Level or Inflammation the Critical Factor for Cardiovascular Disease Risk?

    No orthodoxy lacks accompanying heretics; it often seems that science is a business of proceeding abruptly and messily from one steady state consensus to another via the mechanism of heresy. It is of course worth bearing in mind that most heretics do
    turn out to be wrong, and are consequently forgotten by all but the most painstaking of scientific historians. In the paper I'll point out today, the orthodoxy of blood lipid levels as a cause of cardiovascular disease is challenged. The heresy is to
    suggest that it isn't the lipids at all, but all down to a matter of chronic inflammation.

    This is a tough topic to arbitrate, because raised lipids, such as cholesterol, and raised inflammation go hand in hand. Dietary approaches to tackling cholesterol levels are minimally effective in the grand scheme of things, as dietary content is only a
    small factor in the lipid content of blood, but they also, inconveniently, tend to move the needle on inflammation as well. The calorie content of the diet, considered over the long-term, is linked to lipids and inflammation in equal measures via the
    amount of visceral fat tissue an individual carries. Therapies that are available and widely used to reduce blood cholesterol, such as statins, are shown to have anti-inflammatory effects. Therapies under development, such as delivery of the APOA1
    protein that makes up the HDL particles responsible for dragging cholesterol out of vulnerable cells and transporting it to the liver, also have significant anti-inflammatory effects. You can probably see the challenge.

    On the one hand, it doesn't seem completely unreasonable to mount the argument that lipid levels are a smokescreen, and we should be caring about chronic inflammation. We know that chronic inflammation is very damaging, and contributes to the progression
    of all of the common age-related diseases. When it comes to cardiovascular disease, and particularly atherosclerosis, it seems hard to write off a role for lipid levels in blood, however. Atherosclerosis is caused by oxidized lipids that overwhelm the
    cells sent to clean them up when they irritate blood vessel walls; the fatty deposits that narrow blood vessels are made up of lipids and dead cells. More lipids means more overwhelmed cells. Lower lipid levels means fewer oxidized lipids. But does that
    simple calculus hold up when looked at in detail? To answer that question, we need more data on highly effective therapies that are either anti-lipid or anti-inflammatory, but not both.

    Inflammation, not Cholesterol, Is a Cause of Chronic Disease

    According to the 'cholesterol hypothesis', high blood cholesterol is a major risk factor, while lowering cholesterol levels can reduce risk. Dyslipidaemias (i.e., hypercholesterolaemia or hyperlipidaemia) are abnormalities of lipid metabolism
    characterised by increased circulating levels of serum total cholesterol, LDL cholesterol, triglycerides, and decreased levels of serum HDL cholesterol. High levels of LDL cholesterol and non-HDL cholesterol have been associated with cardiovascular risk,
    while other cholesterol-related serum markers, such as the small dense LDL cholesterol, lipoprotein(a), and HDL particle measurements, have been proposed as additional significant biomarkers for cardiovascular disease (CVD) risk factors to add to the
    standard lipid profile.

    HDL cholesterol has been considered as the atheroprotective 'good' cholesterol because of its strong inverse correlation with the progression of CVD; however, it is the functionality of HDL cholesterol, rather than its concentration that is more
    important for the preventative qualities of HDL cholesterol in CVD. In general, dyslipidaemias have been ranked as significant modifiable risk factors contributing to prevalence and severity of several chronic diseases including aging, hypertension,
    diabetes, and CVD. High serum levels of these lipids have been associated with an increased risk of developing atherosclerosis.

    Furthermore, dyslipidaemias have been characterised by several studies not only as a risk factor but as a "well-established and prominent cause" of cardiovascular morbidity and mortality worldwide. Even though such an extrapolation is not adequate, it
    was, however, not surprising that this was made, because since the term arteriosclerosis was first introduced by pioneering pathologists of the 19th century, it has long been believed that atherosclerosis merely involved the passive accumulation of
    cholesterol into the arterial walls for the formation of foam cells. This process was considered the hallmark of atherosclerotic lesions and subsequent CVD.

    Moreover, one-sided interpretations of several epidemiological studies, such as the Seven Countries Study (SCS), have highlighted outcomes that mostly concerned correlations between saturated fat intake, fasting blood cholesterol concentrations, and
    coronary heart disease mortality. Such epidemiological correlations between dyslipidaemias and atherosclerosis led to the characterisation of atherosclerosis as primarily a lipid disorder, and the "lipid hypothesis" was formed, which would dominate
    thinking for much of the 20th century.

    On the other hand, since cholesterol is an essential biomolecule for the normal function of all our cells, an emerging question has recently surfaced: "how much do we need to lower the levels of cholesterol"? Furthermore, given the fact that cholesterol
    plays a crucial role in several of our cellular and tissue mechanisms, it is not surprising that there are several consequences due to the aggressive reduction of cholesterol levels in the body. Moreover, recent systematic reviews and meta-analyses have
    started to question the validity of the lipid hypothesis, as there is lack of an association or an inverse association between LDL cholesterol and both all-cause and CVD mortality in the elderly.

    The principles of the Mediterranean diet and relevant data linked to the examples of people living in the five blue zones demonstrate that the key to longevity and the prevention of chronic disease development is not the reduction of dietary or serum
    cholesterol but the control of systemic inflammation. In this review, we present all the relevant data that supports the view that it is inflammation induced by several factors, such as platelet-activating factor (PAF), that leads to the onset of
    cardiovascular diseases (CVD) rather than serum cholesterol. The key to reducing the incidence of CVD is to control the activities of PAF and other inflammatory mediators via diet, exercise, and healthy lifestyle choices.

    The Many Possible Influences of the Nucleolus in Aging https://www.fightaging.org/archives/2018/05/the-many-possible-influences-of-the-nucleolus-in-aging/

    The open access review paper I'll point out today covers numerous areas of cellular biochemistry relevant to aging wherein the nucleolus may have a role - though as is always the case, cause and effect in relationships with other aspects of aging are
    hard to pin down. As one might guess, this largely relates to stress responses, quality control, and damage repair within the cell. These line items are important in the way in which the operation of cellular metabolism determines natural variations in
    the pace of aging between species and between individuals within species. While the nucleolus is primarily responsible for building the ribosome structures where proteins are assembled, it has been found to play a part in a wide range of other cellular
    activities. Evolution tends to generate systems in which any given component has many and varied functions, and everything within a cell is connected to everything else.

    This is an example of the broad, dominant class of aging research that is purely investigative. Most research into the detailed mechanisms of degenerative aging is very far removed from any thought of application, and it is lucky happenstance when such
    an opportunity does arise. Systems very closely tied to cellular housekeeping, or responses to stress, or replication seem unlikely to result in the foundations of truly effective therapies. We can look at calorie restriction or exercise, both of which
    alter all of the above items quite profoundly and throughout the body, to see the plausible benefits that might be attained through manipulation of these fundamental aspect of cellular behavior. Searching for means to adjust metabolism to modestly slow
    aging is not a winning strategy; the expected benefits are just not large enough. We must find ways to add decades of vigorous life, not just a few few healthy years.

    Nucleolar Function in Lifespan Regulation

    The nucleolus is an intranuclear organelle primarily involved in ribosomal RNA (rRNA) synthesis and ribosome assembly, but also functions in the assembly of other important ribonucleoprotein particles that affect all levels of information processing.
    Recent evidence has highlighted novel roles of the nucleolus in major physiological functions including stress response, development, and aging. Due to its crucial role in ribosome biogenesis, the nucleolus actively determines the metabolic state of a
    cell. In fact, the size of the nucleolus positively correlates with rRNA synthesis, which in turn is governed by cell growth and metabolism.

    The nucleolus has been regarded as a housekeeping structure mainly known for its role in ribosomal RNA production and ribosome assembly. However, accumulating evidence has revealed its functions in numerous cellular processes that control organismal
    physiology, thereby taking the nucleolus much beyond its conventional role in ribosome biogenesis. Indeed, the nucleolus has been implicated in a number of other important functions including signal recognition particle (SRP) assembly, pre-transfer-RNA (
    tRNA) maturation, RNA editing, telomerase assembly, spliceosome maturation, and genome stability maintenance, thus more generally serving as a critical control site for ribonucleoprotein maturation as well as genome architecture.

    There is also growing evidence ascribing a key role for the nucleolus in aging. Since the discovery of various genes and signaling pathways that regulate lifespan, there has been a dramatic expansion in the research on understanding the biology of aging.
    A number of hallmarks of aging, including genomic instability, telomere attrition, epigenetic modifications, and perturbations in proteostasis have been well established. Recent literature also highlights the crosstalk of different nucleolar functions
    with some of these hallmarks.

    The target of rapamycin (TOR) pathway is a major pathway that integrates inputs on nutrients, growth factors, energy, and stress. When food is plentiful, it promotes cell growth and suppresses recycling processes like autophagy. When food is scarce it
    suppresses growth and promotes autophagy. Notably, TOR inhibition extends lifespan. Active TOR signaling has also been associated with elevated rRNA transcription in multiple studies. The TOR complex stimulates rRNA synthesis in the nucleolus. As
    nucleolar size correlates with rRNA synthesis, the TOR signaling pathway has correspondingly been shown to regulate nucleolar size.

    Ribosome biogenesis is one of the most energy demanding processes in the cell. It is estimated that almost 80% of cellular energy reserves are required for ribosome biogenesis. Major perturbations in the cell have repercussions at the level of ribosome
    biogenesis and conversely, factors involved in ribosome biogenesis can regulate other processes. A number of studies have highlighted the role of ribosomal factors in regulating the lifespan of an organism. Downregulation of genes encoding multiple
    ribosomal proteins has been shown to extend lifespan in yeast and C. elegans. Though it remains to be tested if single ribosomal protein knockdown can have lifespan benefits in vertebrates, there is evidence suggesting that this might be the case.

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