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 scientists.
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
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-mRNA.
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
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 control.
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
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.
The highly repeated structure of the ribsosomal DNA (rDNA) locus and its high rates of transcription make it particularly vulnerable to genome instability and damage. Multiple studies have reported a link between rDNA stability and cellular aging, as well as the association of proteins involved in genome integrity transiting the nucleolus. Aging in yeast is accompanied by nucleolar enlargement and fragmentation, suggesting a mechanism of cellular aging that may be related to nucleolar structure. Concordantly a recent study reported that the premature aging disorder Hutchinson-Gilford progeria syndrome leads to nucleolar expansion and increased ribosome biogenesis. Furthermore, there is evidence suggesting an association of replication stress on rDNA loci with the aging of hematopoietic stem cells, adding more evidence to the general function of the nucleolus in genome integrity and aging.
The nucleolus also impacts other vital cellular processes like the cell cycle and the response to cellular stress. One of the major tumor suppressor proteins central to regulating cell cycle is p53. The nucleolus acts as a platform connecting a cellular stress response with cell cycle through the central tumor suppressor p53. Interestingly multiple studies have implicated p53 in aging in different organisms. The nucleolus has also been associated with regulation of cell senescence. Alterations in nucleolar morphology have been reported in aging cells. In particular, presenescent cells exhibit multiple small-sized nucleoli compared to senescent cells which possess a single enlarged nucleolus.
The perception that the nucleolus is simply the place where ribogenesis takes place has clearly evolved. We now know that it is a highly dynamic organelle that coordinates signals from growth, energy, and stress to the balanced production and assembly of multiple ribonucleoprotein particles and the maintenance of genome integrity. This has ramifications for essentially all levels of molecular organization from genome architecture, RNA metabolism, protein synthesis and quality control to metabolism.
Unexpectedly Better Results Cause Phase III Trial Failure for Gensight
Clinical trials must produce exactly the expected result or they are declared a failure. A clinical trial can fail by producing unexpected benefit, and this has happened to Gensight Biologics' work on allotopic expression of the mitochondrial NH4 gene, aimed at the treatment of inherited retinal degeneration caused by mutation in NH4. Allotopic expression is a process in which a copy of the correctly formed gene is placed into the cell nucleus, suitably altered to enable transport of the protein produced back to the mitochondria where it is need.
In a sane world, this therapy would long ago have been available to anyone willing to accept the risk, based on positive earlier results and lack of serious side-effects. In that same sane world, the therapy would now be available to anyone willing undergo the risk of gaining a greater benefit than was hoped for. Unfortunately we don't live in that world, and Gensight will now have to run further very expensive trials before regulators will permit the treatment to reach the clinic.
We watch progress at Gensight because allotopic expression of NH4 is one-thirteenth of a rejuvenation therapy - Gensight is the result of research supported and encouraged by the Methuselah Foundation some ten years ago. If all thirteen important mitochondrial genes can be copied into the cell nucleus, then that would make an individual largely invulnerable to stochastic mitochondrial DNA damage and resultant dysfunction. It is thought that this is an important root cause of degenerative aging.
GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced topline results from the REVERSE Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment.
Topline results further highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters. Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks.
The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8-22% of patients with the G11778 ND4 mutation. "This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood. The fact that structural measures of the retina showed such a large statistical difference with treatment is compelling and objective evidence that this gene therapy protects the integrity of many retinal ganglion cells from the damage of LHON."
Based on preliminary analysis of the safety data, GS010 was well tolerated after 48 weeks. The ocular adverse events most frequently reported in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation (accompanied by elevation of intraocular pressure in some patients) that is likely related to GS010, and which was responsive to conventional treatment and without sequelae. There were no withdrawals from the trial. GS010 is currently being investigated in two additional ongoing Phase III trials, RESCUE and REFLECT, while patients in REVERSE continue to be followed for another 4 years.
Increased Mitochondrial DNA Copy Number Slows Vascular Aging in Mice
The open access paper here presents an interesting result in mitochondrial biology. Mitochondria are the power plants of the cell, a herd of bacteria-like structures responsible for packaging chemical energy store molecules. They have their own small genome of a few mitochondrial genes. A mitochondrion may have one or several copies of this genome, and mitochondria promiscuously fuse together, divide, and swap around their component parts from one to another. This makes it quite hard to understand how their age-related dysfunction and damage progresses in detail.
Nonetheless, it is well demonstrated that mitochondria become progressively less functional with advancing age, and this is particularly relevant in energy-hungry tissues such as muscles and the brain. Some of this decline may be reaction to forms of cell and tissue damage, and some of this is due to stochastic mutational damage occurring to mitochondrial DNA. In this context, the researchers here show that forcing an increase in the number of copies of mitochondrial DNA can maintain mitochondrial function in old age, and thereby slow vascular aging. It remains unclear, however, as to the exact chain of mechanisms that make this the case: the causes and immediate consequences of an age-related reduction in the number of copies of mitochondrial DNA are not well understood at this point in time.
Mitochondria contain multiple copies of mitochondrial DNA (mtDNA) that encode ribosomal and transfer RNAs and many essential proteins required for oxidative phosphorylation. Loss of mtDNA integrity by both altered mitochondrial DNA copy number (mtCN) and increased mutations is implicated in cellular dysfunction with aging. Reactive oxygen species (ROS), many of which are generated by mitochondria, also increase with age. However, the role of mitochondria in aging may extend beyond ROS, and it is unclear whether decreased mitochondrial function promotes vascular aging directly or is just a consequence of aging.
Aging of the large conduit arteries is a major cause of morbidity and mortality, contributing to hypertension (high blood pressure) and stroke. Currently, it is unclear what the earliest time points that constitute vascular aging in laboratory mice are, which physiological measures of large artery stiffness correspond most closely to humans, and whether similar processes underlie changes in mechanical properties in mouse and human arteries. Aging research is time-consuming and expensive because of the long time courses needed. Therefore, identifying the earliest time points that show the most sensitive and reproducible changes and parameters is crucial in obtaining scientific consensus for mouse models of vascular aging.
We examined multiple parameters of vascular function, histological markers, and markers of mitochondrial damage and function during normal vascular aging, and the effects of reducing or augmenting mitochondrial function on the onset and progression of vascular aging. We identify early, standardized time points and reproducible physiological parameters for vascular aging studies in mice. Vascular aging begins at far earlier time points than previously described in mice, with compliance, distensibility, stiffness, and pulse wave velocity (PWV) being the best discriminators for normal aging and manipulations. Mitochondrial DNA copy number and mitochondrial respiratory function are reduced when functional and structural manifestations of vascular aging begin. Rescue of the copy number deficit observed in normal aging improves mitochondrial respiration and delays all parameters of vascular aging, while reduced mtDNA integrity accelerates vascular aging. Together these data highlight the direct role of mtDNA-mediated mitochondrial dysfunction in the progression of vascular aging.
Improved Approaches to Messing with Metabolism Will Use Gene Therapies
I see that noted geneticist George Church has been discussing his new company Rejuvenate Bio in the media. The projects undertaken there are the logical progression of attempts to slow aging with pharmaceuticals, moving them into the era of gene therapy. This is still guided by the a philosophy of what Aubrey de Grey would call "messing with metabolism." This means that researchers are attempting to alter the amounts of specific proteins in ways that adjust the operation of metabolism into what is hopefully a more optimal state, one in which cell and tissue damage, or the consequences of that damage, accrue more slowly. Gene therapies are far more effective tools than pharmaceuticals when it comes to achieving this outcome with minimal side-effects, and there are many candidate genes to explore.
This is not, however, likely to be as effective as repairing the underlying damage that causes aging. It is tinkering with the broken state of metabolism that arises due to damage, trying to make it more functional without addressing the root cause of its problems. Clearly it is possible to do useful things via this approach, as demonstrated by the existence of statins, first generation stem cell therapies, and the like, but all of these technologies are in principle very limited in comparison to what might be achieved by reversing the root causes of aging.
Professor George Church of Harvard Medical School has co-founded a new startup company, Rejuvenate Bio, which has plans to reverse aging in dogs as a way to market anti-aging therapies for our furry friends before bringing them to us. The company has already carried some initial tests on beagles and plans to reverse aging by using gene therapy to add new instructions to their DNA. If it works, the goal is ultimately to try the same approach in people. "Dogs are a market in and of themselves. It's not just a big organism close to humans. It's something that people will pay for, and the FDA process is much faster. We'll do dog trials, and that'll be a product, and that'll pay for scaling up in human trials."
Church and the team also understand that developing therapies that address aging in humans and getting them approved would not be so easy. It would take too long to prove something worked. "You don't want to go to the FDA and say we extend life by 20 years. They'd say, 'Great, come back in 20 years with the data.'" So, the team has taken a different tack; rather than aiming to increase human lifespan as its main focus, it is instead focusing on the typical age-related diseases common to dogs. The hope is that by targeting the aging processes directly, these diseases could be entirely prevented from developing. If successful, this would lend additional supporting evidence that directly treating aging to prevent age-related diseases could also work in humans.
The lab has been working on a collection of over 60 different gene therapies and has been testing their effects both individually and in combinations. The team intends to publish a report on an approach that extends mouse lifespan by modifying two genes that protect against heart and kidney failure, obesity, and diabetes. Professor Church has commented that the results of this study are "pretty eye-popping". The new startup has been contacting dog breeders, veterinarians, and ethicists to discuss its plans for restoring youth and increasing the lifespan of dogs. Its plan is to gain a foothold in the pet market and then use that as the basis for moving therapies to people.
An Interview with Reason at the Life Extension Advocacy Foundation
Following the launch of Repair Biotechnologies, and since I'll be at the Life Extension Advocacy Foundation's one-day conference, Ending Age-Related Disease, this coming July in New York, I recently answered a few questions and offered a few opinions for the LEAF volunteers. That interview was published yesterday. Regular readers here at Fight Aging! are no doubt all too familiar with many of those opinions already, since I'm not exactly what one might call reticent about putting them forward, but it never hurts to check.
Thanks to the efforts of many advocates, yours included, public perception of rejuvenation is also shifting. How close do you think we are to widespread acceptance?
I don't think acceptance matters - that might be the wrong term to focus on here. Acceptance will occur when the therapies are in the clinic. People will use them, and everyone will conveniently forget all the objections voiced. The most important thing is not acceptance but rather material support for development of therapies. The help of only a tiny fraction of the population is needed to fund the necessary research to a point of self-sustained development, and that is the important thing. Create beneficial change, and people will accept it. Yet you cannot just go and ask a few people. Persuading many people is necessary because that is the path to obtaining the material support of the necessary few: people do not donate their time and funds to unpopular or unknown causes; rather, they tend to follow their social groups.
Presently, rejuvenation is a relatively unknown topic; people who say they're against this technology probably don't think it's a concrete possibility anyway. However, as more important milestones will be reached - for example, robust mouse rejuvenation - this might change. Do you think that these milestones will result in opponents changing their attitudes or becoming more entrenched?
Opposition to human rejuvenation therapies is almost entirely irrational; either (a) it's a dismissal of an unfamiliar topic based on the heuristic that 95% of unfamiliar topics turn out to be not worth the effort when investigated further, or (b) it's a rejection of anything that might result in sizable change in personal opinion, life, and plans, such as the acceptance of aging and death that people have struggled to attain. This sort of opposition isn't based on an engagement with facts, so I think a sizable proportion of these folk will keep on being irrational in the face of just about any scientific advance or other new factual presentation short of their physicians prescribing rejuvenation therapies to treat one or more of their current symptoms of aging.
On the other hand, there will be steady progress in winning people over in the sense of supporting rejuvenation in the same sense as supporting cancer research: they know nothing much about the details, but they know that near everyone supports cancer research, and cancer is generally agreed to be a bad thing, so they go along. Achieving this change is a bootstrapping progress of persuading opinion makers and broadcasters, people who are nodes in the network of society. Here, milestones and facts are much more helpful.
After years of financially supporting other rejuvenation startups, you're now launching your own company focused on gene therapies relevant to rejuvenation. Your company's first objective is thymic regeneration. Why do you think the thymus is the ideal initial target for your work?
It is a very straightforward goal, with a lot of supporting evidence from the past few decades of research. It think it is important to set forth at the outset with something simple, direct, and focused, insofar as any biotechnology project can be said to have those attributes. This is a part of the SENS rejuvenation research agenda in the sense of cell atrophy: the core problem is loss of active thymic tissue, which leads to loss of T cell production and, consequently, immunodeficiency. However, the immune system is so core to the health of the individual that any form of restoration can beneficially affect a great many other systems. The many facets of the immune system don't just kill off invading pathogens; they are also responsible for destroying problem cells (cancers, senescent cells), and they participate in tissue maintenance and function in many ways.
You are using gene therapy; why have you chosen this delivery method specifically and not, for example, a small-molecule approach?
If your aim is to raise or lower expression of a specific protein, and you don't already have a small molecule that does pretty much what you want it to do without horrible side-effects, then you can pay 1-2M for a shot at finding a starting point in the standard drug discovery databases. That frequently doesn't work, the odds of success are essentially unknown for any specific case, and the starting point then needs to be refined at further cost and odds of failure. This is, for example, the major sticking point for anyone wanting to build a small-molecule glucosepane breaker - the price of even starting to roll the dice is high, much larger than the funding any usual startup crew can obtain.
On the other hand, assuming you are working with a cell population that can be transduced by a gene therapy to a large enough degree to produce material effects, then 1-2M will fairly reliably get you all the way from the stage of two people in a room with an idea to the stage of having animal data sufficient enough to start the FDA approval process.
A View of Aging Centered Around Mutation and Senescence
Many researchers see stochastic mutational damage to nuclear DNA as an important mechanism in aging, above and beyond its contribution to cancer risk. The challenge has always been that there don't seem to be enough mutations to explain significant harm, if the harm remains restricted to only the cell in which the mutation occurs. One way to explain how DNA damage causes more general issues is through clonal expansion of detrimental mutations that occur in stem and progenitor cells. Another possible explanation, presently being energetically explored by the research community, is that DNA damage can cause cellular senescence. In this case, just a few senescent cells can cause outsized amounts of harm in surrounding tissue through the potent mix of signals they secrete: generating inflammation, remodeling the extracellular matrix, changing the behavior of other cells for the worse, and so on. We'll be seeing a great many papers like this one in the years ahead, I think.
During an organism's lifetime, cells are constantly exposed to exogenous and endogenous stressful agents. Cells can cope with these stressors by various response mechanisms, or in case of irreversible damage, programmed cell death (apoptosis), or permanent cell-cycle arrest (cellular senescence). Cellular senescence is characterized by a halt in cellular replication, accompanied by a specific molecular phenotype. This phenotype can be the result of a few factors, such as accumulation of DNA damage, telomere attrition, and various epigenetic alterations.
Cellular senescence is one of the cellular pathways contributing to organismal aging. Senescent cells can accumulate in tissues and organs and can ultimately result in tissue lesions that will cause organ dysfunction, such as through the senescence-associated secretory phenotype (SASP). Age-related accumulation of DNA damage has been studied thoroughly, showing correlation between age and damage levels or mutation frequency. In the presence of DNA lesions or abnormalities, the DNA damage response (DDR) is activated and can eventually lead to cell cycle arrest. In older organisms, accumulation of DNA damage and loss of regenerative potential consequently increase the number of senescent cells, leading to aging cells, tissues, organs, and inevitable death.
The accumulation of genomic abnormalities is influenced by the quality of the repair pathways, which may also decline with age. Researchers studied age-related DNA damage in peripheral blood cells using single nucleotide polymorphism (SNP) microarray data from over 50,000 individuals. The frequency of detectable genomic abnormalities was low (less than 0.5%) at birth and rose to 2-3% in 50-year-old donors. Peripheral blood cells were also studied using whole-exome sequencing data from DNA of 17,182 individuals lacking hematologic phenotypes. Somatic mutations were rare in young donors (~40 years old) but became more frequent with age. Furthermore, while studying subjects at 70-79 years, compared with 90-108 years, mutation frequency rose from 9.5 to 18.4%, respectively.
In conclusion, the connection between DNA damage and aging is emphasized by the secretion of senescence-associated proteins during cellular senescence, a phenotype which is activated by DNA damage and is common for both human and mice. Though much progress has been achieved, full understanding of these mechanisms has still a long way to go.
XPO1 as a Novel Target for Therapies to Enhance Autophagy
Autophagy is the name given to a collection of cellular housekeeping processes that recycle damaged and unwanted proteins and structures inside a cell. Most of the means of slowing aging demonstrated in laboratory species involve increased autophagy: it is an important response to any form of stress likely to result in more damage inside the cells. The less damage there is, the better off the cells. This in turn can leads to a longer, healthier life span to some degree. It is also worthy of note that autophagy declines with age, and this is though important in a range of age-related conditions.
Autophagy enhancement therapies have been on the research community agenda for a long time now. There have been scores of papers published on this topic in the last decade alone, even putting to one side the point that all calorie restriction mimetic development is likely based on increased levels of autophagy somewhere under the hood. Unfortunately, means of directly enhancing autophagy have not as yet made it out of the lab; there has been very little progress towards the clinic. This is worth bearing in mind when reading publicity materials of the sort presented here. It is little different in tone from similar items published many years ago, and which subsequently went nowhere.
The process of autophagy involves the rounding up of misfolded proteins and obsolete organelles within a cell into vesicles called autophagosomes. The autophagosomes then fuse with a lysosome, an enzyme-containing organelle that breaks down those cellular macromolecules and converts it into components the cell can re-use. Researchers wanted to see if they could increase autophagy by manipulating a transcription factor (a protein that turns gene expression on and off) that regulates autophagic activity. In order for the transcription factor to switch autophagic activity on, it needs to be localized in the nucleus of a cell. So the team screened for genes that enhance the level of the autophagy transcription factor, known as TFEB, within nuclei.
Using the nematode C. elegans, the screen found that reducing the expression of a protein called XPO1, which transports proteins out of the nucleus, leads to nuclear accumulation of the nematode version of TFEB. That accumulation was associated with an increase in markers of autophagy, including increased autophagosome, autolysosomes as well as increased lysosome biogenesis. There was also a marked increase in lifespan among the treated nematodes of between about 15 and 45 percent.
The next step was to see if there were drugs that could mimic the effect of the gene inhibition used in the screening experiment. The researchers found that selective inhibitors of nuclear export (SINE), originally developed to inhibit XPO1 to treat cancers, had a similar effect - increasing markers of autophagy and significantly increasing lifespan in nematodes. The researchers then tested SINE on a genetically modified fruit fly that serves as a model organism for the neurodegenerative disease ALS. Those experiments showed a small but significant increase in the lifespans of the treated flies.
As a final step, the researchers set out to see if XPO1 inhibition had similar effects on autophagy in human cells as it had in the nematodes. After treating a culture of human HeLa cells with SINE, the researchers found that, indeed, TFEB concentrations in nuclei increased, as did markers of autophagic activity and lysosomal biogenesis. "Our study tells us that the regulation of the intracellular partitioning of TFEB is conserved from nematodes to humans and that SINE could stimulate autophagy in humans. SINE have been recently shown in clinical trials for cancer to be tolerated, so the potential for using SINE to treat other age-related diseases is there."
Is the Architecture of the Nuclear Envelope Fundamental to the Evolution of Aging?
Hydra are functionally immortal, given a suitably static environment. They exhibit continual proficient regeneration, and their mortality risk is low and constant over time. As a species they appear near unique in this. Why is aging and imperfect regeneration almost universal among species? One explanation is that environmental change gives aging species an advantage: non-aging species can certain emerge in eras of comparative environmental stability, but will be out-competed when the environment shifts. Other explanations involve the more complex structure in higher species, particularly in the central nervous system, where data must be stored as lasting molecular and cellular structures. Long-term persistence of fine cellular structure and proficient, continual regeneration don't go well together.
This study looks at the complexity and structure of the nuclear envelope inside cells as a possible dividing line between the few immortal species such as hydra and all of the others. The authors propose that increased complexity of the nuclear structure, and thus its greater vulnerability to certain kinds of molecular damage known to be associated with aging, limits the degree to which longevity and highly proficient regeneration can evolve - though I think that this is certainly something that could be argued either way, and at length.
The freshwater polyp Hydra represents a rare case of an animal with extreme longevity. It demonstrates unlimited clonal growth with no detectable signs of senescence, such as age-dependent increase in mortality or decrease in fertility, and thus is considered as non-senescent. Hydra body is made of cells of three lineages, originating from unipotent ectodermal and endodermal epithelial stem cells, and from multipotent interstitial stem cells. In contrast to most other animals, stem cells in Hydra indefinitely maintain their self-renewal capacity, thus sustaining non-senescence and everlasting asexual growth.
While unlimited self-renewal capacity of the stem cells is long recognized fundamental for Hydra's non-senescence, the underlying molecular mechanisms remain poorly understood. So far, the transcriptional factor FoxO was found as critical regulator of Hydra stem cell homeostasis and longevity, supporting the view that components of the insulin/insulin-like growth factor signaling pathways govern lifespan throughout the animal kingdom. Several other transcriptional factors are supposed to contribute to the non-aging of Hydra. However, the putative effector molecules downstream from these transcriptional factors that might contribute to the sustained stem-cell activity and non-senescence in Hydra remain unclear.
Studies in bilaterian animals propose proteins of the Lamin family to be the major effector molecules involved in the age-related cellular senescence and, hence, in the genetic control of ageing and lifespan. These highly conserved intermediate filament proteins form a complex network at the inner nuclear membrane, arrange the nuclear architecture and orchestrate multiple nuclear processes, such as DNA replication and repair, chromatin condensation, and transcription. Importantly, bilaterian cells are highly sensitive to the nuclear lamina disturbances. Decline in the expression level of Lamin B1 and increase of an aberrant Prelamin A isoform are associated with the age-dependent alterations in the nuclear lamina morphology and chromatin organization observed upon physiological ageing in mammals and invertebrates.
A homologue of vertebrate lamin B genes has been identified in Hydra, yet no efforts have been reported addressing the role of Lamin in cnidarian longevity. Here we present detailed analysis of the single Hydra lamin gene (hyLMN), its expression pattern, and distribution and function of its protein product (HyLMN). We demonstrate that proliferation of stem cells in Hydra is robust against the disturbance of Lamin expression and localization. While Lamin is indispensable for Hydra, the stem cells tolerate overexpression, downregulation, and mislocalization of Lamin, and disturbances in the nuclear envelope structure. This extraordinary robustness may underlie the indefinite self-renewal capacity of stem cells and the non-senescence of Hydra. A relatively low complexity of the nuclear envelope architecture might allow for the observed extreme lifespans of Hydra, while an increasing complexity of the nuclear architecture in bilaterians resulted in restricted lifespans.
Alcor Receives 5 Million Donation
Today's good news is that the Alcor Life Extension Foundation, one of the two oldest US cryonics providers, has received a 5 million donation. Like a number of recent donations in our broader community, this originates from an individual who has done well in the growth of cryptocurrencies. I think that this philanthropy is a sign of things to come; these newly wealthy individuals are, on balance, younger and less set in their ways than those who come to wealth via the slower and more traditional means. They will be, accordingly, more adventurous, more disruptive, more supportive of causes that have a high utility but are not yet mainstream. This is all to the good, I feel.
This donation is an enormous sum for the non-profit cryonics community - it is a significant fraction of the existing Alcor assets, near all of which are locked up to support the long-term commitments of providing for its members. Cryonics is just as important to the cause of minimizing human death as the forms of medical biotechnology more usually featured here at Fight Aging! Sadly, it is also far worse off when it comes to the available resources, particular in the very necessary endeavor of research and development, to improve the state of the art, and produce a viable, self-sustaining industry based on reversible low-temperature storage of tissues. I would like to see this state of affairs change for the better, and this donation is a sizable first step on that road.
I am delighted to announce that Alcor has received a stunning 5,000,000 contribution to fund cryonics research. Alcor member Brad Armstrong (A-3000), came to visit Alcor in November 2016. After a tour and long and fascinating chat, before he left I suggested that he finally sit down and sign the membership paperwork. We would provide the witnesses and the Notary Public. 90 minutes later, Brad was done and handed us a check, making him a member. (See? It's not as difficult as you think.)
Fast forward to April 2018. Brad's assistant called to say that Brad wanted to make a major contribution to Alcor for the purposes of cryonics research. When I called Brad, I was immediately reminded that he is a down-to-earth, easygoing fellow who wants cryonics to work and is eager to fund what he knows matters. Brad is an enthusiast of cryptocurrencies and an admirer of Hal Finney - the first recipient and early developer of Bitcoin - and an Alcor member cryopreserved in August 2014. The 5 million research contribution is being held in the name of the "Hal Finney Cryonics Research Fund".
On behalf of Alcor and the cryonics effort in general, I want to say thank you. But how can I possibly express those thanks adequately? With a gift of this magnitude comes the responsibility of managing and spending it wisely for maximum impact. Until the Alcor board and Research Group determine how best to hold and use this funding, I have moved it from Alcor's bank account into a money market fund. Stay tuned as we determine how to use this remarkable influx of funding to boost Alcor's cryonics research.
A Review of Growth Hormone in Aging
The author of this open access review of the study of growth hormone in aging is one of the eminent experts in this part of the field, noted for work on various loss of function mutant mice, lacking either functional growth hormone or functional growth hormone receptor genes. The current record for mouse longevity is held by a growth hormone knockout variant: these mice wouldn't survive in the wild, as they are small and vulnerable to cold, but they live 60-70% longer than their unmodified peers in the laboratory.
It is well documented that circulating levels of GH decline with age in various mammalian species, including humans, domestic dogs, and laboratory rodents. Yet in laboratory mice, disruption of growth hormone (GH) signaling leads to a remarkable extension of longevity. These findings were hard to interpret and were originally received with some skepticism because they implied that normal actions of a hormone have significant 'costs' in terms of longevity, and that a gross defect in the functioning of the endocrine system can have striking benefits for healthy survival. However, the evidence that absence of GH signaling extends longevity of mice is strong, reproducible, and now generally accepted.
Several aspects of the findings in GH-deficient and GH-resistant mice deserve particular emphasis. First, the significant extension of longevity in these animals is reproducible and not limited to a particular laboratory, diet, or genetic background. Second, lifespan is extended in both females and males. Third, extension of longevity is associated with a similarly striking extension of healthspan. Fourth, the magnitude of the increase in longevity exceeds the effects of most genetic, pharmacological, or dietary interventions that have anti-aging effects in mice.
A recent study examined longevity of mice lacking both GH and functional GH receptors. While these tiny 'double mutants' were remarkably long-lived compared to their normal siblings, they did not live significantly longer than mice lacking only GH or only GH receptors. In females, survival curves of GH-deficient Ames dwarf, GH-resistant GHRKO, and 'double mutant' (df/KO) animals were nearly identical.
The importance of GH signaling in the control of murine lifespan is further emphasized by the evidence that disruption of signaling events 'downstream' from GH and its receptor also extends longevity. Early findings of extended longevity of female mice heterozygous for the deletion of IGF-1 receptor were confirmed and extended in further studies. Major increase of longevity was seen in mice in which amount of bioavailable IGF-1 was reduced at the tissue level by germline or adult disruption of the gene coding for pregnancy associated plasma protein A, an enzyme degrading IGF-1 binding protein. Significant and reproducible extension of longevity was also produced by pharmacological suppression of the activity of mechanistic target of rapamycin, a kinase regulated by GH and IGF1.
Importantly, conclusions concerning pro-aging effects of normal or elevated GH based on studies in mutant, gene knockout, transgenic, or drug treated mice appear to apply to genetically normal mice and to other mammalian species. Multiple studies reported negative association of adult body size (a strongly GH- and IGF-1-dependent trait) with longevity in comparisons of different mouse strains, selected lines, and individual animals.
The Damage Done by a Lack of Exercise, and Digging Yourself Out of the Hole
How much harm is done - and how quickly - by failing to maintain an exercise program? How long does it take to reverse those consequences? No-one has the final answer to those questions, firm numbers derived from the way in which the human body functions. We can look at the results of studies such as this one with some interest, however. We might compare this with studies of weight and mortality, in which the evidence suggests that lasting harm is done by carrying excess fat tissue over years, even if lost later.
By analyzing reported physical activity levels over time in more than 11,000 American adults, researchers conclude that increasing physical activity to recommended levels over as few as six years in middle age is associated with a significantly decreased risk of heart failure. The same analysis found that as little as six years without physical activity in middle age was linked to an increased risk of the disorder. "In everyday terms our findings suggest that consistently participating in the recommended 150 minutes of moderate to vigorous activity each week, such as brisk walking or biking, in middle age may be enough to reduce your heart failure risk by 31 percent. Additionally, going from no exercise to recommended activity levels over six years in middle age may reduce heart failure risk by 23 percent."
The researchers caution that their study was observational, meaning the results can't and don't show a direct cause-and-effect link between exercise and heart failure. But the trends observed in data gathered on middle-aged adults suggest that it may never be too late to reduce the risk of heart failure with moderate exercise. "Unlike other heart disease risk factors like high blood pressure or high cholesterol, we don't have specifically effective drugs to prevent heart failure, so we need to identify and verify effective strategies for prevention and emphasize these to the public." There are drugs used to treat heart failure, such as beta blockers and ACE inhibitors, but they are essentially "secondary" prevention drugs, working to reduce the heart's workload after dysfunction is already there.
The researchers used data already gathered from 11,351 participants in the long term Atherosclerosis Risk in Communities (ARIC) study, recruited from 1987 to 1989. The participants' average age was 60, and 57 percent were women. Participants were monitored annually for an average of 19 years for cardiovascular disease events such as heart attack, stroke, and heart failure using telephone interviews, hospital records and death certificates. Over the course of the study there were 1,693 hospitalizations and 57 deaths due to heart failure.
In addition to those measures, at the first and third ARIC study visits (six years apart), each participant filled out a questionnaire, which asked them to evaluate their physical activity levels, which were then categorized as poor, intermediate or "recommended," in alignment with guidelines issued by the American Heart Association. The "recommended" amount is at least 75 minutes per week of vigorous intensity or at least 150 minutes per week of moderate intensity exercise. One to 74 minutes per week of vigorous intensity or one to 149 minutes per week of moderate exercise per week counted as intermediate level activity. And physical activity qualified as "poor" if there was no exercise at all.
Heart failure risk decreased by about 12 percent in the 2,702 participants who increased their physical activity category from poor to intermediate or recommended, or from intermediate to recommended, compared with those with consistently poor or intermediate activity ratings. Conversely, heart failure risk increased by 18 percent in the 2,530 participants who reported decreased physical activity from visit one to visit three, compared with those with consistently recommended or intermediate activity levels.