Fight Aging! Newsletter, June 8th 2015

June 8th 2015

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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  • A Glance at the State of Virotherapy as a Cancer Treatment
  • An Example of General Interest Writing on Aging and the Prospects for Treatment
  • Quantifying the Disease Risk of Aging
  • Recent Considerations of Stem Cells and the Aging Process
  • Changes in the Senescence-Associated Secretory Phenotype or Failing Immune Surveillance?
  • Latest Headlines from Fight Aging!
    • The Vascular Secret of Klotho
    • The Longevity of daf-2 and clk-1 Mutants Depends Upon tts-1
    • Decellularization as a Way to Expand the Donor Organ Pool
    • Towards Salivary Gland Regeneration
    • Decellularization to Prepare an Entire Limb for Transplant
    • More on the Development of Recellularized Lungs
    • Spreading Realizations on the Future of Retirement
    • Investigations of HIF-1a in MRL Regenerator Mice
    • DNA Damage as a Necessary Mechanism
    • If Aiming to be Cryopreserved, Don't Make Things Hard For the Provider Organization


The future of cancer treatments is, one way or another, all about two things: (a) the ability to identify and target common mechanisms in a broad range of cancers so that one technology platform, one research initiative, can be useful for many patients rather than just a few, and (b) targeting cancer cells so that treatments are far more effective and have few and negligible side-effects. Today's cancer treatments are highly specific to cancer types and subtypes, the result of a large number of parallel lines of development undertaken at great cost, and are also damaging to the patient's healthy tissue. At the most blunt even the application of the best of chemotherapies are an art that involves finding the optimal point in the range lying between too little to degrade the cancer and too much for the patient to bear. Yet the transition is underway to a world in which cancer treatments are something you walk into a clinic to obtain, and walk right out again a hour later feeling no worse for the experience.

There are many ways in which this goal might be achieved, coupling the knowledge needed to distinguish the chemistry of cancer cells from ordinary cells with any one of a number of possible delivery systems. Over the past decade researchers have demonstrated the use of nanoparticle assemblies that glue together sensors for cancer cell characteristics and cell-killing compounds, but why build new molecular machinery when there so much of the stuff is already evolved and waiting to be used as raw materials? Take immune cells, for example, which already handily perform the function of attacking and destroying unwanted cells and other invaders. The use of engineered and trained immune cells is prevalent in modern cancer research, and trials of immunotherapies for cancer are in some cases a fair way along the road to widespread clinical availability. This may well win out to be the basis for most of the next generation of cancer treatment technology.

Beyond immunotherapies, however, there are bacteria and viruses to consider. These can also be engineered to attack cancer cells in a discriminating fashion, and self-replication is a powerful weapon in the therapeutic arsenal if it can be harnessed and controlled. While receiving less attention than immunotherapy these days, there are still a goodly number of impressive demonstrations in the laboratory of the ability of bacteria and viruses to mop up cancer when everything goes right. In clinical trials, there are still hurdles to overcome far more often than not, but it is perhaps encouraging that the same was true for immunotherapies not so very long ago.

Personalized virotherapy in cancer

The use of engineered oncolytic viruses (OVs) is a promising new therapy for cancer treatment. Different OVs have been engineered to express immune stimulatory molecules indicating that OVs can act at two levels, by directly killing malignant cells in concurrence with the simultaneous activation of the host anti-tumor immunity. OVs can be also combined with chemotherapeutic agents providing an aggressive platform for cancer attack. One of these OVs, a Herpes Simplex virus named T-VEC armed with GM-CSF has just completed a phase III trial in advanced melanoma with promising results and might reach the clinic after FDA approval.

Conditionally Replicative Adenoviruses are oncolytic adenoviruses (OAV) engineered to selectively replicate within and kill tumor cells. Selectivity is obtained through the use of ''cancer cell''-specific promoters (CCSP) that are selected to replace viral promoters and drive the expression of genes essential for OAV replication. OAVs replicate essentially in malignant cells with positive expression of the gene from which the CCSP was selected. OAVs efficacy can be also improved through the exchange of the capsid fiber of the virus or addition of specific moieties that will retarget vectors to enter the cell through alternative receptors.

As for other therapeutic modalities, viral spread and therapeutic efficacy is hampered by the extracellular matrix (ECM) barrier. The high resistance to conventional and targeted therapies in desmoplastic tumors of adults is largely due to the dense ECM. The ECM distorts blood and lymphatic vessels structure that hampers the possibility of systemically delivered therapies to reach the tumor mass. With this in mind, we started engineering OAVs whose replication was driven by CCSPs active both in the stroma and in the malignant compartment of the tumor mass. More recently we have shown that the OAV AV25CDC combined with gemcitabine exhibited a large efficacy and complete absence of toxicity in preclinical models of pancreatic cancer in mice and syriam hamsters. AV25CDC was able to disrupt tumor architecture by inducing an increase in MMP-9 activity that would have facilitated gemcitabine penetration deeply inside the tumor mass.


It is always pleasant to see more people writing seriously about aging and medicine, even if they omit what I see as some of the important viewpoints, or fail to end up advocating for massive funding of SENS research so as to make best speed towards an end to age-related frailty and disease. Certainly all too few people are willing to make that last leap at the moment. However, that there is more interest these days in treating aging as a medical condition and in the biological details of aging is a sign that the tide of public awareness is rising. In turn this should mean that it will become ever easier to raise funds in the years ahead - certainly I hope so, since I'll be doing my part to try to pull in grassroots funding for some of the more important lines of early-stage research.

At the grand scale this is all about persuasion, as is the case for all bootstrapped advocacy for a cause. You might recall a scientific study published a few years back on the tipping point of inevitability: where is the line that divides an opinion that remains forever fringe from an opinion that will become mainstream? The researchers suggested that the division is somewhere near 10% of the populace. I think we're getting there for important sections of the public when it comes to support for the medical control of aging in the same sense as the presently mainstream support for the medical control of cancer. Progress along this road accelerates rapidly as the tipping point nears, which is certainly a relief after the painfully slow early stages of talking people around to see common sense on medicine and aging, one individual at a time, and with frequent rejection. Certainly these past two years have seen things moving along at a much faster pace than the decade that preceded them.

Why We Age - Part I: The Evolution Of Aging

If you had to guess how you were going to die, you could narrow it down pretty quickly. It takes only a handful of diseases to account for over half of the deaths of Americans each year. Only five in fact - heart disease, cancer, stroke, Alzheimer's disease, and diabetes. Though these disparate diseases affect different organ systems and develop as a result of different mechanisms, they all share a common underlying cause - the aging of the human body. It is aging that is the real killer here - aging kills more people on Earth than anything else. Maybe that's obvious, maybe it's not.

For a condition that kills so many, most of us don't have the slightest understanding of how aging works or why it happens. This series will ask the deceptively simple question, "Why do we age?" To tackle this, we will break this question into three distinct parts: "Why do we age?", "How do we age?", and "Is it possible to live longer?" The first will explore aging from the perspective of evolution, the second will delve into the actual mechanisms within our bodies that cause us to age, and the third will discuss scientific research into lifespan extension.

Why We Age - Part II: A Comprehensive View Of The Aging Process

In general, the biological theories of aging can be split into two types: stochastic and programmed (stochastic just means random). Stochastic theories suggest that damage to our cellular components accumulates over time, leading to functional decline, and ultimately, death. On the other hand, programmed theories propose that aging arises from a set biological timetable, possibly the same one that regulates childhood growth and development.

Though stochastic and program theories are frequently presented as mutually exclusive, in reality they are connected, complementary, and deeply embedded in the interwoven, complex biological network that regulates all of life. To foster a holistic appreciation for the aging process, I will first layout the various theories of aging, and will then connect the pieces to construct a comprehensive map of aging.

Why We Age - Part III: Can We Live Forever?

Amazingly, the most widely studied method of lifespan extension requires no drugs, no supplements, no organ replacement. All that is required is reducing your caloric intake - just eat less. This practice, known as calorie restriction, has been observed to extend the lifespan of many species, from yeast to mice. Remarkably, initial findings have even shown that it can decrease the onset of age-related diseases in primates as well. To be clear, calorie restriction does not mean starving yourself, just reducing your caloric intake from a baseline level, typically by around 30%.

So why does calorie restriction work? From an evolutionary perspective, it is thought that in times of famine, organisms forgo reproducing, instead holding out for more prosperous times. As a result, it is advantageous to up-regulate genes involved in protection and repair and wait for better days to come. Essentially, we have specific genes that sense the availability of nutrients in the environment, and in times of scarcity, slow the process of aging, so that we may reproduce in more favorable conditions.


Some of the decay of aging is going to happen no matter what you choose do on a day to day basis. Your metabolism is running all the time, and it constantly generates damage as a byproduct of that activity. Metabolic waste accumulates in long-lived cells and in the extracellular matrix. Stochastic DNA damage builds up in the cell nucleus to raise cancer risk and in mitochondria to cause dysfunction there. Cells react to damage and dysfunction by becoming senescent or declining in activity. You could live the perfect life and all of this and more will happen regardless: it is wear and tear as a consequence of the evolved structure of your biology.

There is plenty you can do to hurry this along, however. Happenstance and choices made can accelerate existing forms of damage or add new types of damage that make the situation worse, bringing you to a state of being physically older at a given chronological age than would otherwise have been the case. We tend to live longer than our ancestors in part because we've managed to eliminate a large fraction of the burden of infectious disease and the long-term harm it causes to survivors, for example. Our wealth and technology also provides the opportunity to become fat and sedentary in greater numbers, however, which accelerates the pace of damage, and smoking of course merits a chapter of its own in the annals of killing yourself slowly.

So there is primary aging and there is secondary aging. Primary aging is the damage you can do next to nothing about at the moment, and will only be impacted by the development of therapies capable of repairing the accumulation of damage that causes degenerative aging and all of its attendant medical conditions. Secondary aging is what you do to yourself, most people through some combination of excess fat tissue, lack of exercise, and smoking, and is consequently under your control. The balance of influence here is obviously biased towards primary aging in the end: you can't make lifestyle choices that reliably allow you to live to age 90 in the environment of today's medical technology. Three-quarters of people with the best health are dead by that age, and only medical progress will change that statistic.

You can, however, make simple choices that shift your life expectancy across the range of a decade, out there in the future ahead. You can change your future health for the better and reduce your expected medical expenses at the same time. It seems worth making that effort, especially at this time of very rapid development in biotechnology: a few years here or a few years there might mean the difference between being alive to benefit from the first effective clinical rejuvenation treatments, or dying just on the cusp of that new age of medicine. You never know, and certainly there are those of us trying to speed up the development of those rejuvenation treatments.

Here is an interesting approach to putting some better numbers on the split between primary and secondary aging. All too many people focus on secondary aging when it comes to their health, and that is where their concerns and vision stop. But if we want to see significant progress in funding and support for effective treatment of the causes of aging, then it is very necessary to convince more of these individuals that they are overlooking the most important part of the problem:

Information Theoretical Analysis of Aging as a Risk Factor for Heart Disease

Non-communicable chronic diseases are the greatest cause of mortality in the world, yearly claiming more than 34.5 million lives worldwide (66% or 2/3 of global deaths, or nearly 100,000 deaths daily). Hence major efforts are directed toward their alleviation. Yet, a crucial point is often missing in these considerations, namely, the due emphasis on the fact that these diseases are age-related diseases, and their main risk factor is not necessarily related to environmental risks or life-style choices, but to the aging process itself! There is an appreciation that the incidence of non-communicable diseases increases with age steeply, unlike the effects of other environmental and life-style factors whose influence may be considered steady. Yet, the exact weight of age in relation to other risk factors remains uncertain. Hence, there is a need to be able to determine this weight in order to provide a fuller diagnostic and prognostic assessment for age-related diseases and design interventions that would be able to affect the entire array of risk factors.

Such an ability would be especially valuable for heart disease, the main age-related disease and cause of death in the world. As of 2010, it was estimated that the cardiovascular and circulatory diseases represented the largest proportion among all causes of mortality. Yet, it is also known that cardiovascular diseases, and ischemic heart disease in particular, can be highly susceptible to therapeutic and lifestyle interventions, capable of dramatically extending the health and longevity of the subjects. Hence it is of primary importance to be able to assess the entire array of risk factors as well as the effects of therapeutic interventions on the risk factors, either individually or in combinations, including age. If age is the main risk factor, then it may well be that the primary target of the therapeutic and lifestyle intervention would be the aging process itself.

Here we apply the information theoretical measure of normalized mutual information (uncertainty coefficient) to determine precisely the weight of various risk factors in heart disease, and the particular weight of age as a risk factor, individually and combined with other factors. We show that individual parameters, including age, often show little correlation with heart disease. Yet in combination, the correlation improves dramatically. For diagnostic parameters specific for heart disease the increase in the correlative capacity thanks to the combination of diagnostic parameters, is less pronounced than for the less specific parameters. Age shows the highest influence on the presence of disease among the non-specific parameters and the combination of age with other diagnostic parameters substantially improves the correlation with the disease status. Hence age is considered as a primary "metamarker" of aging-related heart disease, whose addition can improve diagnostic capabilities.

There is a growing realization that a promising and cost-effective strategy to combat severe non-communicable diseases is to give a greater focus of health research from attempting to address individual diseases and symptoms to addressing their underlying root cause and main risk factor - the degenerative process of aging. Such an approach has already yielded in the past valuable strategies to combat non-communicable diseases. Historical examples include probiotic diets, cell therapy and adjuvant immunotherapy that were born from biological research of aging. Further emphasis on treating, delaying or even reversing the seemingly "general" and "systemic" biological processes of aging may likely produce not just a general improvement of the functional state of the aged, but also further advances in the treatment of specific age-related non-communicable diseases, such as heart disease. The current work, for the first time quantitatively demonstrating the weight of age (aging) as a risk factor for heart disease, gives further support to this approach. It further emphasizes the need to intervene into the basic aging processes for developing effective therapies for age-related diseases.


Investigation of the contribution of stem cells to the process of degenerative aging is a flourishing field of research. As we age our stem cell populations gradually cease their activity, spending more time in periods of quiescence, and becoming more damaged by the wear and tear of continued metabolic activity. The principal role of stem cells is to provide a supply of new cells to keep tissues in working order, and diminished supply results in growing frailty and dysfunction. This is one of the causes of disease and death due to aging.

There are reasons for optimism, however. The stem cell research field is collectively one of the largest and most active scientific institutions in the world today. At present there are many possible avenues towards the development of therapies to slow or reverse those aspects of aging that are directly caused by growing stem cell dysfunction and quiescence. Further, since so many of the first generation regenerative therapies emerging from the study of stem cells are intended to treat age-related diseases, researchers in this field have a strong incentive to find and address all of the major age-related issues associated with stem cell biochemistry. They have to tackle these challenges in order to assure the effectiveness of their stem cell treatments. That said, this is of course only one of a number of fields that must all become this energetic and well funded if we are to see significant progress towards a comprehensive toolkit of rejuvenation therapies, many of which are far removed indeed from that level of support.

It is nonetheless encouraging to see progress on a near weekly basis reported in publications and the press. The latest issue of Cell Stem Cell features a number of open access papers on the role of stem cells in aging, illustrative of a range of current directions in research. I think you'll find them interesting:

Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline?

Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived, and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not. It is also unclear how evolutionary theories of aging that are currently accepted as at least plausible can be reconciled with the biological properties of somatic stem cells.

It is proposed here that somatic stem cell maintenance mechanisms lead to preferential accumulation, rather than disposal, of damaged stem cells. On the other hand stringent selection in the germline renders this lineage seemingly immortal. Furthermore, use of glycolysis for ATP production in somatic stem cells as opposed to mitochondrial respiration in the germline suggests that mitochondria play a critical role in stem cell maintenance and gamete selection. This hypothesis is consistent with prevailing evolutionary theories of aging, and with a critical role for mitochondria in aging.

Stem Cell Aging and Sex: Are We Missing Something?

A glance at the list of the human individuals currently living over the age of 110 - supercentenarians - reveals a surefire strategy for achieving such exceptional longevity: be female. Out of the 53 living supercentenarians, 51 are female. No other demographic factor comes remotely close to sex in predicting the likelihood of achieving such an advanced age. Sexual dimorphism with respect to longevity is a characteristic of most mammals and has been recorded in human populations since at least the mid-18th century. This dichotomous capacity for resilience has inspired wide-ranging hypotheses to explain the underlying mechanisms. It also raises questions regarding the sexual dimorphism of processes known to sustain tissue regeneration and function throughout life, including adult stem cell renewal.

Most adult stem cell populations undergo an age-related decline, leading to dysfunctional tissue homeostasis, which most likely participates in defining the ultimate lifespan of the organism. Interestingly, sex-specific regulation of stem cell populations has been demonstrated for several stem cell types, and it has long been appreciated that many canonical aging pathways exhibit sex specificity. However, despite the seeming interrelationship between sex, stem cell maintenance, and aging, few studies have sought to directly explore the interaction of these three variables. Here we discuss the sexual dimorphism of adult stem cell populations and how processes regulating the aging of stem cells may also be modified by sex.

Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency

Pluripotent stem cells (PSCs) are characterized by their ability to extensively self-renew and differentiate into all the cell types of the body. We propose PSCs cells as a novel model for studying human aging. Unlike traditional aging paradigms that focus on endpoints such as longevity or the restoration of regenerative capacity, PSCs allow us to monitor and manipulate molecular and cellular hallmarks of aging during both reprogramming and cell differentiation. Capturing the timing and sequence of the steps involved in cellular rejuvenation offers a unique opportunity for subsequent mechanistic studies.

The strong evidence for cellular rejuvenation during induced pluripotent stem cell (iPSC) induction indicates that many aspects of aging are reversible and may represent epigenetic rather than genetic barriers in biology. Therefore, a future is conceivable wherein it will be possible to reliably rejuvenate somatic cells without the need to move them back to pluripotency. In addition to studying rejuvenation, it will be equally important to identify novel induced aging strategies. The ability to direct both cell fate and age in iPSC-derived lineages will allow modeling of human disorders at unprecedented precision. Such studies could yield more relevant disease phenotypes and define novel classes of therapeutic compounds targeting age-related cell behaviors. The ability to program and reprogram cellular age on demand will present an important step forward on the road to decoding the mystery of aging.

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

The incidence of tissue dysfunction, diseases, and many types of cancer, including colorectal cancer and some types of leukemia, exponentially increases with age, and aging represents the single biggest risk factor for most cancers. However, the reasons for this aging-associated failure in tissue maintenance and the increase in cancer are poorly understood. Without a doubt, cancer is largely driven by genome dysfunction, frequently exemplified by specific genetic alterations that drive one or more specific cancer phenotypes. Overwhelming evidence indicates that the genesis and progression of cancer depend on accumulation of genetic alterations.

There is emerging evidence that aging induces changes in molecular pathways that accelerate the initiation and/or clonal dominance of mutations in stem and progenitor cells. The tight connection between aging-associated accumulation of stem and progenitor cell mutations with the failure of tissue maintenance and cancer suppression indicates a causal relationship between these factors. In addition to the cell-intrinsic mechanisms discussed here, there is increasing evidence that cell-extrinsic factors affect stem cell maintenance and possibly the selection of mutant stem and progenitor cells during aging. Likely, and potentially exciting, extrinsic candidates include aging-associated defects in the stem cell niches, alterations in the systemic/blood circulatory environment, changes in proliferative competition among stem and progenitor cells, inflammatory responses, and defects in immune surveillance of damaged cells. The delineation of this interplay of cellular and molecular mechanisms that contribute to the initiation and selection of stem and progenitor cell mutations in the context of aging will undoubtedly help the development of therapies aiming to improve early detection, prevention, and risk assessment of aging-associated diseases, organ dysfunction, and cancer.


Cells can become senescent in reaction to a variety of environmental stresses or forms of damage, activating a program that halts cellular replication and triggers the generation of a mix of potent signals that can influence surrounding cells and tissue structure, a state known as the senescence-associated secretory phenotype (SASP). Senescent cells have a role in embryonic development, controlling the shaping of tissues at the extremities, such as the growth of fingers. Their existence in adults is perhaps because the same mechanism, particularly the arrested growth aspect of it, serves to suppress cancer risk - or at least it does so initially and while senescent cells are present in only modest numbers. Evolution tends to lead to complex systems in which every component part is reused in many ways.

Among the signals making up SASP there are those that encourage the immune system to destroy senescent cells, should those cells fail to trigger their own programmed cell death processes. The immune system has its own issues that manifest during the aging process, however, and it becomes ever less effective at all of its tasks, whether that is protecting the body from invading pathogens or destroying unwanted and potentially dangerous native cells. Over a lifetime ever more of the cells in our tissues become senescent and linger rather than being cleared out. Their collective SASP grows in influence, degrading tissue function and contributing greatly to age-related frailty and disease. With enough senescent cells present the original outcome of cancer suppression is swept away and the toxic environment begins to encourage cancer formation.

There is a great deal yet to learn about the nature of the senescent state, exactly why senescent cells accumulate, and how their presence contributes to specific manifestations of age-related disease. There is enough detail yet to be mapped to keep a much larger research community than presently exists occupied for decades. Fortunately all of that can be skipped over if a good way of clearing senescent cells can be developed: periodically remove these cells and you remove the problem. That is a much less complex proposition than reaching a full understanding of senescence, and builds on research already well advanced in other parts of the medical research establishment: how to identify types of cell reliably from their distinctive chemistry, and how to selectively destroy them without harming their neighbors. Cancer researchers are making good progress towards achieving those goals for the types of cell they are interested in, and many of the technologies will be adaptable to senescent cells.

Back to the learning, however. Do we accumulate senescent cells because the immune system falls down on its job? Or it is a matter of there being numerous subtly different types of senescent state, some of which only come into play in a meaningful way in later life? Or perhaps the nature of SASP changes with age for other reasons, such as a reaction to other forms of cellular and tissue damage. At this point any of that might be plausible - and while all interesting, it can all be bypassed by the senescent cell clearance short cut to removing that contribution to degeneration aging. While parts of the aging research community are interesting in removing senescent cells, parts of the cancer research community are interesting in the possibility of creating more of them as a cancer therapy, however. That requires learning enough about senescence to be able to tread the fine line between suppressing and encouraging cancer, and it is not simply a matter of the number of senescent cells present. One thing that is emerging from the intersection of cancer research and senescent cell research is that there is a lot of room to tinker with the mechanisms involved:

The usual SASPects of liver cancer

Cellular senescence is a stable form of cell cycle arrest that limits the propagation of damaged cells and can be triggered in response to diverse forms of cellular stress. This anti-proliferative program was initially considered a cell-autonomous mechanism that promotes tumor suppression and tissue homeostasis. However, several groundbreaking studies performed in the last decade have established that senescent cells can impact their environment through the secretion of growth factors, cytokines, chemokines, immune modulators and extracellular matrix-degrading enzymes. This process, collectively known as the senescence-associated secretory phenotype (SASP), enables the non-cell-autonomous activities of senescent cells. The functions exerted by the SASP are diverse and include the autocrine reinforcement of cell cycle arrest as well as the paracrine transmission of the senescent phenotype to neighboring cells, thereby maintaining and propagating tumor suppression. Moreover, SASP can directly modulate the tissue microenvironment, elicit immune surveillance of senescent cells, and paradoxically, promote tumorigenesis by supporting the proliferation of surrounding malignant or pre-malignant cells.

Many of the findings that illustrate the impact of SASP on the microenvironment stem from in vivo studies in the liver. Upon liver injury, hepatic stellate cells (HSCs) activate, proliferate, and develop a profibrotic secretome. Activated HSCs eventually undergo cellular senescence and produce a SASP enriched in fibrolytic molecules, contributing to fibrosis resolution. Moreover, senescent HSCs also secrete pro-inflammatory cytokines that direct the immune surveillance of senescent HSCs, further limiting liver fibrosis. The production of a proper SASP and subsequent immune-mediated clearance of senescent cells appear to be critical for the beneficial effects of cellular senescence on liver homeostasis and tumor suppression. Accordingly, genetic or chemical abrogation of the immune system leads to increased liver fibrosis, liver cancer, and delayed tumor regression after p53 reactivation in liver cancer cells. Intriguingly, in a murine model of HCC driven by a chemical carcinogen and obesity, senescence of HSCs and the corresponding SASP were associated with hepatocarcinogenesis. These contradictory findings could potentially be explained by differences in the senescence trigger, in the composition of the SASP, or by defective senescence surveillance. In fact, the clearance of senescent HSCs was not observed in the latter study, further emphasizing the importance of efficiently eliminating senescent cells.

Pro-senescence therapy has recently emerged as a novel therapeutic approach for treating cancer and could be applied to liver cancer, a disease that lacks effective treatment. However, if senescent tumor cells are not properly eliminated by the immune system, the SASP can promote the growth of non-senescent adjacent tumor cells. One solution could be to manipulate SASP to restrict its protumorigenic properties and/or enhance its ability to engage the immune system. An elegant work clearly showed how Pten-loss-induced senescence creates an immunosuppressive and protumorigenic microenvironment in prostatic intraepithelial neoplasias. However, pharmacological inhibition of the Jak2/Stat3 pathway reprogrammed SASP, restoring immune surveillance and the anti-tumor effects. Another appealing option is to boost the immune system to improve the surveillance of senescent tumor cells. Treatment with the anti-programmed cell death protein 1 (PD1) immune checkpoint antibodies or ipilimumab, an antibody that enhances the activation of cytotoxic T cells by blockade of the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) receptor, could improve the anti-tumor potential of pro-senescence therapies. Understanding and manipulating the signaling pathways that control SASP as well as identifying the key mediators of SASP will be essential to unleash the full potential of the senescence program.


Monday, June 1, 2015

The klotho enzyme can be manipulated to slow aging in laboratory animals, and more circulating klotho is associated with enhanced cognitive function. Like many of the mechanisms found to modestly slow aging in short-lived species in the laboratory, the activities of klotho touch on many systems in the body and are far from completely cataloged. This is an example of some of the more speculative areas of investigation:

Klotho-deficient mice manifest a phenotype resembling accelerated human ageing. Klotho-deficient mice have a short lifespan, and overexpression of Klotho in mice extends lifespan significantly in comparison with normal mice, which is taken as proof of the concept that Klotho is associated with longevity. In a human population study, Klotho gene variations were found to be associated with life extension. Of particular interest was the finding that Klotho deficiency in mice was associated with a severe vascular phenotype of arteriosclerosis, impaired endothelial function, and impaired angiogenesis.

Klotho protein in mammals is present in different isoforms, as a membrane-bound protein and as a soluble form. Membrane Klotho confers tissue target specificity for FGF23. The function of Klotho as an obligatory coreceptor for FGF23 explains the nearly identical phenotypes that are observed in knockout mice lacking either Klotho or FGF23. Soluble Klotho is secreted into serum, urine, and cerebrospinal fluid. Serum Klotho or Klotho fragments can have humoral actions on tissues far distant from the site of biosynthesis. This is based on the observation of generalized involvement of tissues and organs outside the Klotho expression tissues in the prematurely ageing phenotype of Klotho-deficient mice and on the finding that administration of soluble Klotho ameliorated the premature ageing-related features, such as growth retardation, organ atrophy, and vascular calcification.

Experimental studies have shown that soluble Klotho, when delivered as a humoral factor, can protect the vasculature. Klotho gene delivery by adenoviral vector increased endothelium-dependent nitric oxide synthesis and prevented adverse vascular remodeling in an arteriosclerotic, obese rat model. Results from several in vitro models point toward a direct effect of soluble Klotho on vascular tissue. Recently, soluble Klotho has been shown to regulate vascular tonus, and a nitric oxide stimulatory ability was confirmed in vitro.

Uremia is potentially a state of Klotho deficiency based on decreased concentrations both at the tissue level and in the circulation, although determinations of serum Klotho levels are problematic. It is of high priority to better understand whether deficiency of Klotho contributes to the reduced longevity and other many severe complications in patients with chronic kidney disease, which are accompanied by a dramatic increase in the rate of cardiovascular morbidity and death.

In different experimental models soluble Klotho has been shown to protect against acute kidney injury, renal fibrosis, uremic cardiomyopathy, vascular calcification, and endothelial dysfunction. These observations are very important not only to understand the pathogenetic mechanisms involved, but also with respect to the development of future and more effective treatments and prophylactic measures, including replacement/substitution of the potentially missing hormone. In this context it is essential to know whether the uremic state is associated with reduced circulating levels of Klotho, whether local vascular production is reduced, and whether vascular tissue is an additional source of humoral Klotho. It is still an open question whether Klotho is present in the vasculature under physiological conditions, and, if so, whether it is changed in the uremic state.

Monday, June 1, 2015

Since little if anything works in isolation inside a cell, many of the varied methods discovered over the past twenty years to modestly slow aging in laboratory species are in fact acting on a much smaller set of underlying mechanisms. Thus a steady flow of new discoveries like the one below continue to take place, a step by step exploration of the vast complexity of metabolism that will likely still be far from done by the time viable rejuvenation technologies exist, built based on a repair approach that bypasses the need for a complete understanding of cellular biochemistry in aging:

Long noncoding RNAs were until recently thought to exist and function predominantly in the nucleus. It is now fast becoming realized that they effusively associate with cytosolic ribosomes. Several functions for short noncoding RNAs bound to ribosomes have been described, such as those that derive from both mRNAs and tRNAs and function as stress-induced inhibitors of protein translation. It is thus becoming clear that ncRNAs, both short and long, are playing roles in protein translation that are only beginning to be fully appreciated.

The biogenesis of ribosomes and their coordination of protein translation consume an enormous amount of cellular energy. As such, it has been established that the inhibition of either process can extend eukaryotic lifespan. Here, we used next-generation sequencing to compare ribosome-associated RNAs from normal strains of Caenorhabditis elegans to those carrying the life-extending daf-2 mutation. We found a long noncoding RNA (lncRNA), transcribed telomeric sequence 1 (tts-1), on ribosomes of the daf-2 mutant. Depleting tts-1 in daf-2 mutants increases ribosome levels and significantly shortens their extended lifespan. We find tts-1 is also required for the longer lifespan of the mitochondrial clk-1 mutants but not the feeding-defective eat-2 mutants. In line with this, the clk-1 mutants express more tts-1 and fewer ribosomes than the eat-2 mutants.

The precise mechanism of the tts-1 lncRNA remains to be determined. One intriguing possibility is that it is specifically regulating the translation of ribosomal protein mRNAs. Supporting this notion is the observation that despite the marked reduction of ribosomal proteins in the daf-2 mutant proteome, expression levels of ribosomal protein mRNAs in the daf-2 mutants are actually higher than in wild-types. This suggests that a specific block of ribosomal protein gene expression at the level of translation is imposed in mutants undergoing lifespan extension, and we believe this will be an interesting area of future study. In sum, we propose that the tts-1 lncRNA is able to reduce ribosome levels in a manner that is necessary for lifespan extension. Since many recent reports demonstrate that both genetic and pharmacological manipulations of the translation machinery can extend longevity in eukaryotes, our study puts lncRNAs forward as a compelling area in the field of aging research.

Tuesday, June 2, 2015

It isn't widely appreciated that many of the organs donated for transplant are discarded as unsuitable. In the near future tissue decellularization will be used to expand the pool of viable organs, though it may also lead to enabling xenotransplantation of organs farmed from pigs or other large animals, a step that would largely remove present limits on available organs. In the longer term decellularization and donor organs, human or animal, will be replaced by the growth of complex tissues such as whole organs on artificial scaffolds or completely from scratch, starting only with cells. For now, however, decellularization is the hot topic:

Researchers report progress in their quest to build replacement kidneys in the lab. The teams' goal is to make use of the more than 2,600 kidneys that are donated each year, but must be discarded due to abnormalities and other factors. The scientists aim to "recycle" these organs to engineer tailor-made replacement kidneys for patients. The process begins by washing the discarded organs in a mild detergent to remove all cells. The idea is to replace these cells with a patient's own kidney stem cells, making a tailor-made organ that would not be rejected and wouldn't require the use of powerful anti-rejection medication. But are the organs a suitable platform for engineering after going through the process to remove cells?

To help answer that question, the researchers evaluated whether the washing process affects a small sac of capillaries in kidneys called the glomerulus. The researchers screened the kidney structures to see if they retained growth factors that play an important role in function. The research team reports that the size, structure and function of the micro-vessels in the glomerulus are preserved after the cell-removal process. In addition, vital proteins known as growth factors that regulate cell growth and function are retained within the kidney structures. "These growth factors play a vital role in the formation of new vessels and kidney cells. The fact that they are preserved means they can potentially facilitate the repopulation of cells into the structure and reduce the potential of clot formation."

In a separate study, the team reported on the interactions that occur when stem cells are placed on kidney structures that have been through the cell removal process. The team seeded stem cells derived from amniotic fluid onto sections of kidney structures. In this first study to describe the long-term results of this process, the scientists observed that the stem cells proliferated when placed on the structures and were functionally active as demonstrated by the fact that they secreted chemicals and growth factors involved in such critical pathways as inflammation and the formation of new blood vessels. "These results indicate that discarded human kidneys are a suitable platform for engineering replacement kidneys and that when cells are added, the structures behave as an effective and viable biosystem."

Tuesday, June 2, 2015

Tissue engineering is a field of many diverse research groups, each specializing in just a few types of tissue or organ structures. There is a great deal going on, and some of it is out of the public eye simply due to language barriers and the fact that more obscure or less important tissues are involved. It all still needs to be done, however: all of the body fails with age, and thus all tissues are a target for regenerative treatments. Take the work of this Japanese research group, for example:

Salivary gland hypofunction, or xerostomia (dry mouth syndrome), induces various clinical problems, such as dental decay, bacterial infection, and swallowing dysfunction. Xerostomia caused by autoimmune disease and aging affects an increasing number of patients. The development of novel functional treatments for xerostomia is needed, as currently available therapies are only palliative in nature. Tissue stem cell transplantation and gene therapy are currently being investigated as potential approaches to the restoration of salivary gland function. The final goal of regenerative therapy is fully functional regenerative organ replacement for dysfunctional organs.

Previously, we developed a technology to reconstitute the organ germ (Organ Germ Method) using epithelial and mesenchymal stem cells. We have recently reported the regeneration of fully functional organs, such as teeth, hair and lacrimal glands, can be achieved by the transplantation of bioengineered organ germs. In this review, we describe the regeneration of the salivary gland as part of a feasibility study of a next-generation regenerative therapy.

Wednesday, June 3, 2015

Decellularization is a process that strips all the cells from tissue leaving behind the extracellular matrix and its chemical guides. If suitably repopulated with new cells from a patient, the optimal result is living and fully functional tissue matched for transplantation without the possibility of immune rejection. This approach is a stepping stone on the way to generating new complex tissues from scratch, a way to work around the fact that the research community cannot yet produce artificial scaffolds of sufficient complexity and quality to match the natural extracellular matrix structure present in organs. Most work on decellularization to date has involved internal organs such as hearts, livers, and lungs, but there is no reason why it cannot be applied to a limb, as is the case here:

Researchers have used an experimental approach previously used to build bioartificial organs to engineer rat forelimbs with functioning vascular and muscle tissue. They also provided evidence that the same approach could be applied to the limbs of primates. "The composite nature of our limbs makes building a functional biological replacement particularly challenging. Limbs contain muscles, bone, cartilage, blood vessels, tendons, ligaments and nerves - each of which has to be rebuilt and requires a specific supporting structure called the matrix. We have shown that we can maintain the matrix of all of these tissues in their natural relationships to each other, that we can culture the entire construct over prolonged periods of time, and that we can repopulate the vascular system and musculature."

The same decellularization process used in whole-organ studies - perfusing a detergent solution through the vascular system - was used to strip all cellular materials from forelimbs removed from deceased rats in a way that preserved the primary vasculature and nerve matrix. After thorough removal of cellular debris - a process that took a week - what remained was the cell-free matrix that provides structure to all of a limb's composite tissues. At the same time, populations of muscle and vascular cells were being grown in culture.

The research team then cultured the forelimb matrix in a bioreactor, within which vascular cells were injected into the limb's main artery to regenerate veins and arteries. Muscle progenitors were injected directly into the matrix sheaths that define the position of each muscle. After five days in culture, electrical stimulation was applied to the potential limb graft to further promote muscle formation, and after two weeks, the grafts were removed from the bioreactor. Analysis of the bioartificial limbs confirmed the presence of vascular cells along blood vessel walls and muscle cells aligned into appropriate fibers throughout the muscle matrix.

Functional testing of the isolated limbs showed that electrical stimulation of muscle fibers caused them to contract with a strength 80 percent of what would be seen in newborn animals. The vascular systems of bioengineered forelimbs transplanted into recipient animals quickly filled with blood which continued to circulate, and electrical stimulation of muscles within transplanted grafts flexed the wrists and digital joints of the animals' paws. The research team also successfully decellularized baboon forearms to confirm the feasibility of using this approach on the scale that would be required for human patients.

Wednesday, June 3, 2015

Work on decellularizing different types of tissues to produce patient-matched donor organs proceeds at different rates. Some are much harder than others, not in the step of removing cells from the donor organ, which is fairly consistent for all tissue types, but in the development of methodologies to repopulate the tissue with all of the necessary cell types while ensuring that the correct tissue structures are produced. Last year researchers demonstrated a first pass at recellularized lungs, and suggested that there is a decade to go yet before they'll be ready for human use. More work is underway:

A promising option to increase the donor organ pool is to use allogeneic or xenogeneic decellularized lungs as a scaffold to engineer functional lung tissue. Decellularization of mouse, rat, goat, sheep, pig, non-human primate and human lung tissue has been accomplished, and resulted in three-dimensional acellular scaffolds that are generally devoid of detectable residual DNA. Repopulation of decellularized lungs has been reported using a number of different cell types. However, only partial recellularization of alveoli, airways and pulmonary vasculature has been achieved.

One potential approach to improve recellularization of decellularized lung scaffolds is to use the dynamic rotating wall vessel (RWV) bioreactor, which has been shown to promote growth and differentiation of stem and/or epithelial cells. The RWV is an optimized form of continuous suspension culture wherein cells are cultured in horizontally rotating bioreactors that are completely filled with media. The bioreactor rotation offsets sedimentation, creating a constant, gentle fall of cells and their growth substrate/scaffolds through the culture medium.

We demonstrate that decellularized mouse lungs recellularized in a rotating wall vessel contained more cells with decreased apoptosis, increased proliferation and enhanced levels of total RNA compared to static recellularization conditions. These results were observed with two relevant mouse cell types: bone marrow-derived mesenchymal stromal (stem) cells (MSCs) and alveolar type II cells. In addition, MSCs cultured in decellularized lungs under static but not bioreactor conditions formed multilayered aggregates. Gene expression and immunohistochemical analyses suggested differentiation of MSCs into collagen I-producing fibroblast-like cells in the bioreactor, indicating enhanced potential for remodeling of the decellularized scaffold matrix. In conclusion, dynamic suspension culture is promising for enhancing repopulation of decellularized lungs, and could contribute to remodeling the extracellular matrix of the scaffolds with subsequent effects on differentiation and functionality of inoculated cells.

Thursday, June 4, 2015

The future of retirement in a world of radical life extension achieved via rejuvenation treatments is that there will be no more retirement in the traditional sense. Retirement as an institution exists because of unavoidable frailty and disease in aging, and those outcomes will be ended through progress in medicine. The research and development programs that create effective rejuvenation treatments will take place over less than half a lifetime once things really get going. All too many people today are unaware of the potential for progress towards the medical control of aging, entering their professional careers expecting their lives to have the same shape and duration as those of their grandparents. At least some are waking up, however:

Human life has reached an inflection point - one that matters a great deal for those planning for retirement. People are living longer and trying to stretch their income to make ends meet and stay ahead of inflation, but that's not the inflection point financial advisors are really concerned about - that's just the everyday blocking and tackling on behalf of client portfolios. The emerging challenge goes way beyond that.

Scientists have found the mechanisms that govern aging and are already doing experiments in rats on how to reverse it. They've found species that do not die of old age, such as the jellyfish Turritopsis. "We're adding three months to life per calendar year. It's not an if, it's a when, and the point in time is in the 15- to 20-year range. In a decade or two, or three, there will be a class of people taking treatments who can live for a long time, and that affects employment planning, retirement planning ... Society will never have seen that before. The first person to reach age 150 has already been born. How do I talk to a client preparing to retire at 65 using the traditional model and with planning software that only goes to age 95? The financial model is broken."

The shift from a linear to a cyclical lifeline is already starting to be seen: The average American at age 35 has already had eight jobs. "It's not going to be birth, school, job, retirement, death," he said. Soon individuals will cycle between work, school, sabbaticals, more schooling and more work in a cycle that has never before existed. "It's going to be less about money in the future and more about the future. How do you sit down with someone in their 30s or 40s and tell them that they are going to live to 110 or 120 and haven't prepared financially for that?" At first the challenge won't be that the information is overwhelming; it's that the client won't even believe what the advisor is saying, making it the most difficult and potentially costly conversation an advisor needs to initiate. "They will look at you like you are smoking crack. It's the singularity conversation, and if they think an advisor is crazy, then the advisor will lose the client."

Thursday, June 4, 2015

The MRL mouse lineage is capable of unusual levels of tissue regeneration for a mammal, an entirely accidental discovery that emerged from an unrelated research program some years ago. Since this came to light, research groups have been chasing down the potential mechanism, and for much the same reason as scientists are interested in the details of salamander regeneration: the possibility of developing therapies to enhance human healing processes. Last I heard, the gene p21 was involved in MRL mouse regenerative capacity, but here researchers are proceeding down a different track, one that seems to have a fairly direct path to a first pass at a regenerative therapy for humans:

"We discovered that the HIF-1a pathway - an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development - can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration." The discovery is the latest development in a long investigation sparked by a chance observation in an unusual mouse strain. Almost 20 years ago, researchers noticed that the MRL mouse can spontaneously regenerate cartilage and other tissues after injury, making it a rare exception among mammals. Years of subsequent research involving the MRL mouse led the researchers to theorize that the HIF-1a pathway, which helps cells respond to low oxygen conditions, may also hold the key to the unique regenerative capability of MRL mice.

Under normal oxygen conditions, HIF-1a is degraded by prolyl hydroxylases (PHDs). Stabilization of HIF-1a levels can be accomplished through inhibition of PHDs. To test their theory, the researchers first experimentally down-regulated HIF-1a in MRL mice, which they found led to a loss of regenerative capability in the mice. Next, they selected a non-regenerating strain of mice to see what would happen when they experimentally up-regulated (stabilized) HIF-1a levels after an ear hole punch injury. The mice received three injections of a PHD inhibitor in a slow-release formulation at 5-day intervals. After 30 days, the researchers observed ear hole healing with closure and regrowth of cartilage and new hair follicles. In addition, the drug-treated mice showed a pattern of molecular changes indistinguishable from that observed in MRL mice during regeneration in response to injury, confirming HIF-1a as a central driver of healthy regeneration of lost or damaged tissue in mice.

"Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a. Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a." The researchers plan to move ahead to modify the drug delivery system to achieve an ideal formulation, which they will use to investigate regrowth potential in many types of tissues.

Friday, June 5, 2015

Researchers here present the intriguing possibility that the same very same nuclear DNA damage that may be a contribution to degenerative aging is also an essential part of cellular operation in some vital tissues and processes:

Each time we learn something new, our brain cells break their DNA, creating damage that the neurons must immediately repair. This process is essential to learning and memory. "Cells physiologically break their DNA to allow certain important genes to be expressed. In the case of neurons, they need to break their DNA to enable the expression of early response genes, which ultimately pave the way for the transcriptional program that supports learning and memory, and many other behaviors." However, as we age, our cells' ability to repair this DNA damage weakens, leading to degeneration. "When we are young, our brains create DNA breaks as we learn new things, but our cells are absolutely on top of this and can quickly repair the damage to maintain the functionality of the system. But during aging, and particularly with some genetic conditions, the efficiency of the DNA repair system is compromised, leading to the accumulation of damage, and in our view this could be very detrimental."

In previous research into Alzheimer's disease in mice, the researchers found that even in the presymptomatic phase of the disorder, neurons in the hippocampal region of the brain contain a large number of DNA lesions, known as double strand breaks. They discovered that of the 700 genes that showed changes as a result of this damage, the vast majority had reduced expression levels, as expected. Surprisingly though, 12 genes - known to be those that respond rapidly to neuronal stimulation, such as a new sensory experience - showed increased expression levels following the double strand breaks. To determine whether these breaks occur naturally during neuronal stimulation, the researchers then treated the neurons with a substance that causes synapses to strengthen in a similar way to exposure to a new experience. "Sure enough, we found that the treatment very rapidly increased the expression of those early response genes, but it also caused DNA double strand breaks."

Finally, the researchers attempted to determine why the genes need such a drastic mechanism to allow them to be expressed. Using computational analysis, they studied the DNA sequences near these genes and discovered that they were enriched with a motif, or sequence pattern, for binding to a protein called CTCF. This "architectural" protein is known to create loops or bends in DNA. In the early-response genes, the bends created by this protein act as a barrier that prevents different elements of DNA from interacting with each other - a crucial step in the genes' expression. The double strand breaks created by the cells allow them to collapse this barrier, and enable the early response genes to be expressed. "Surprisingly then, even though conventional wisdom dictates that DNA lesions are very bad - as this 'damage' can be mutagenic and sometimes lead to cancer - it turns out that these breaks are part of the physiological function of the cell."

Friday, June 5, 2015

The small and largely non-profit cryonics industry provides indefinite low-temperature storage immediately following death, so as to preserve the fine structure of neural tissue that stores the data of the mind. For so long as that data remains intact, the possibility remains for the future development of medical molecular nanotechnologies capable of restoring a preserved individual to active life. It is an unknown chance at a future life, but infinitely better than all the other alternatives for those who do not have the time to wait for the defeat of degenerative aging. It is sad and barbaric that cryonics remains on the margins of our society while near all of those who die vanish into oblivion. In a better world they could have been saved.

It is also sad and barbaric that laws in most regions of the world prevent the coordination of death and cryopreservation at a time of the patient's own choosing. Euthanasia is forbidden, leaving patients to suffer horribly in their final weeks, and ensuring that the process of cryopreservation is much more expensive and uncertain than it might otherwise be, involving standby teams and scrambling at short notice to put a complex medical procedure into action. Speed is essential in order to prevent neural damage, but the uncaring laws preventing euthanasia make that hard to do well in all circumstances. Many people understand all of this and do what they can to organize a good cryopreservation over months and years in advance, but there are always those who do not. The cryonics organizations frequently go above and beyond, but why make their lives hard and introduce additional uncertainty and delay when you don't have to? You are the one who will suffer for it in the end.

Mariette Selkovitch, Alcor member A-2830, was pronounced clinically dead on Tuesday May 5, 2015 at 1:30 am in California. Mrs. Selkovitch, a neurocryopreservation member, became Alcor's 136th patient later the same day.

Around 1:16am on Tuesday May 5, 2015, we received an alert from Ronald Selkovitch, a 21-year member of Alcor. His wife, Mariette, had gone into cardiac arrest and resuscitation was being attempted. There was no membership paperwork for her and no funding arranged but he was insisting that we come for her. Normally, the absence of prior arrangements would rule out Alcor accepting such a case. However, on checking our records, some important details emerged. Something similar happened in 2008, when Mr. Selkovitch's 101-year old mother died, also without having any membership paperwork signed or funding arranged. Nevertheless, we accepted the case. Mr. Selkovitch followed through as promised and paid for her. His mother is still our oldest patient at time of clinical death, just short of 102 years old.

Medical Response Director, Aaron Drake, contacted Suspended Animation to put them on the alert. However, SA's Suspension Services manager said that (especially given that any team would likely arrive post-mortem) SA would not deploy without complete paperwork and agreement from the board and from Alcor's Chief Medical Advisor, Dr. Steven Harris. I called and was able to consult with a majority of directors in the middle of the night and secure agreement from everyone, along with Dr. Harris, but the shortage of time meant that it would be impossible to fulfill the conditions for SA and so Alcor deployed a team directly.

It must be stressed that the decision could easily have gone the other way, and in just about any other circumstance, would have. As it was, due to this being a third-party signup (by a member), Mr. Selkovitch was faced with the standard third-party fee (the primary purpose of which is to compensate for family and legal risks). He said he would gladly cover this if we would accept his wife's case. We were fortunate in that the sheriff said that no autopsy was needed and she would be released immediately to a mortuary (the same one where his mother was taken in 2008). The one living son of Mr. and Mrs. Selkovitch was on his way and Mr. Selkovitch said he was on the way there and would very likely sign the Relative's Affidavit (which he did). Mr. Selkovitch was diligent in that he filled out the membership paperwork that I gave Aaron to take with him. Funding followed very rapidly.

The Alcor team set out for California at 5:21 am and were able to administer and circulate medications while packing the head in ice. The team returned to Alcor with Mrs. Selkovitch at 7:38 pm. Cryoprotective perfusion was ended at 12:13 am on May 6 and cool down immediately initiated.


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