Cytomegalovirus Presence Expands Considerably in Old Age
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The open access paper referenced here expands the picture of cytomegalovirus and the aging immune system with additional data. Cytomegalovirus (CMV) is a common herpesvirus present in near everyone by the time old age rolls around. In the majority of people it presents no symptoms, but it is apparently an important factor in the age-related decline of the immune system. Like all herpesviruses it cannot be effectively cleared from the body, and over the years the immune system devotes ever more of its limited resources to uselessly fighting it. An old immune system contains legions focused on cytomegalovirus and all too few cells capable of responding to other pathogens. This is one of the contributing causes of immunosenescence, the progressive failure of the immune system with age.

The best approaches to solving this problem actually involve expanding the population of useful immune cells rather than getting rid of cytomegalovirus. Clearing it doesn't fix the damage done: the specialized cells are already specialized. So possible treatments might involve delivering infusions of immune cells grown from the patient's own stem cells, selectively destroying cytomegalovirus-targeted immune cells to free up space for replacement with new immune cells, or restoring the thymus to increase the pace at which new immune cells are created.

Cytomegalovirus infection has been associated with a variety of health problems in elderly people and there is increasing interest in the mechanisms that underlie this association. A key determinant in this regard will be greater understanding of the balance of the viral load and the host immune response during healthy ageing. In this study we report, for the first time, that the level of cytomegalovirus viral load within the blood increased markedly in elderly people. A novel feature of our work was the use of digital droplet PCR (ddPCR) to provide an accurate quantitative measure of latent viral DNA. Previous methods for detection of CMV generally relied on nested PCR techniques, which made quantification challenging and also raised substantial problems with reproducibility.

Our work was performed using DNA isolated from monocytes, which are established as the most important haemopoietic site of viral latency. The first interesting finding was the observation that CMV was detectable in only a minority of donors, as 64% of people remained negative by ddPCR despite the presence of chronic infection as confirmed by CMV-specific IgG positivity. Indeed, in younger people below the age of 50 years, the detection of CMV load in the blood was uncommon, being observed in only 13% of donors tested. The lower limit of detection provided by ddPCR in our assay was for a single copy of virus within the total reaction volume and as such a negative result indicated absent or extremely low levels of virus. This low level carriage may reflect a lower intrinsic probability of viral reactivation in younger donors but is perhaps more likely to reflect the consequence of effective immune surveillance of viral replication in younger individuals.

The frequency of viral detection increased markedly with each decade above the age of 50 years to 37.5% and 50% and finally became positive in every donor who was older than 70. Interestingly the amount of viral DNA detected within the blood also increased substantially with age with a 29 fold increase observed between donors aged less than 70 and those over this age. The use of nested PCR also detected viral DNA within the majority of healthy elderly donors. These data indicate that a gradual impairment in the ability to control CMV load within blood starts around the age of 50 years and then deteriorates markedly beyond the age of 70. In conclusion, these data reveal the delicate balance that has evolved between chronic CMV infection and the host immune response and indicate that this symbiosis can break down during ageing, where an increase in CMV viral load occurs as the attritional effects of chronic surveillance and the impact of immune senescence become more apparent. It is likely that increased understanding of the clinical importance of chronic viral infection on human health will become an important health consideration in future years.


Poor Fitness Correlates with Later Smaller Brain Volume
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The results of this study can be added to the many reasons to keep up with a decent level of exercise. A sedentary lifestyle has costs, most of which manifest as a greater risk of age-related disease in later later:

Poor physical fitness in middle age may be linked to a smaller brain size 20 years later. "We found a direct correlation in our study between poor fitness and brain volume decades later, which indicates accelerated brain aging." For the study, 1,583 people enrolled in the Framingham Heart Study, with an average age of 40 and without dementia or heart disease, took a treadmill test. They took another one two decades later, along with MRI brain scans. The researchers also analyzed the results when they excluded participants who developed heart disease or started taking beta blockers to control blood pressure or heart problems; this group had 1,094 people.

Exercise capacity was estimated using the length of time participants were able to exercise on the treadmill before their heart rate reached a certain level. For every eight units lower a person performed on the treadmill test, their brain volume two decades later was smaller, equivalent to two years of accelerated brain aging. When the people with heart disease or those taking beta blockers were excluded, every eight units of lower physical performance was associated with reductions of brain volume equal to one year of accelerated brain aging. The study also showed that people whose blood pressure and heart rate went up at a higher rate during exercise also were more likely to have smaller brain volumes two decades later. People with poor physical fitness often have higher blood pressure and heart rate responses to low levels of exercise compared to people with better fitness.


Proposing a Microbial Cause of Alzheimer's Disease, Again
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The biochemistry of the brain is enormously complex and still poorly understood at the detail level. This is also true of the mechanisms of Alzheimer's disease. Treating Alzheimer's is, more or less, the unified banner under which the research community raises funds to map and catalog the brain. It is why so much funding pours into the study of this one condition in comparison to others. In the research mainstream it is expected that only with much greater understanding of neurobiology will effective therapies emerge. Since the molecular biology involved is so very complicated, there are many gaps into which new theories of disease progression can fit without much challenge. Building theories is a lot easier and cheaper than running studies, and so there will always tend to be more theorizing than construction of potential therapies. This is especially true when, as is the case today, the dominant paradigm of amyloid clearance has yet to produce results despite years of trials. Perhaps that indicates it is harder than expected, or perhaps it indicates that it is a wrong direction.

Some of the more interesting alternative theories include the idea that amyloid clearance channels in tissues close to the brain fail with age for many of the same reasons that blood vessels accumulate damage in aging issues. This is a putative cause and possible fix for increasing amyloid levels. The Methuselah Foundation is funding a test of that theory, as such a test should be cheap and fairly conclusive one way or another.

Another set of theories argues that Alzheimer's has a meaningful microbial contribution to its development, that progression of the condition is sped up by exposure to fungal and other pathogens. In the paper here, this is presented as a new category of Alzheimer's disease rather than as a contributing factor to a single unified condition called Alzheimer's. I think it pretty likely that Alzheimer's will be formally split up into categories in the years ahead. Neurobiochemistry is a big enough space to fit numerous distinct paths leading to a similar end result in which aggregates like amyloid overrun the brain and harm its cells, and that seems a more likely reality than one path.

Inhalational Alzheimer's disease: An unrecognized - and treatable - epidemic

Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Type 3 is very dissimilar to the other two types, and may be mediated by a fundamentally different pathophysiological process (although, by definition, still β-amyloid positive and phospho-tau positive): the onset is typically younger (late 40s to early 60s); ApoE genotype is usually 3/3 instead of 4/4 or 3/4; the family history is typically negative (or positive only at much greater age); symptom onset usually follows a period of great stress, sleep loss, anesthesia, or menopause/andropause; presentation is not predominantly amnestic but is instead cortical, with dyscalculia, aphasia, executive dysfunction, or other cortical deficits; and the neurological presentation is often preceded by, or accompanied by, depression.

Over the past two decades, elegant work has demonstrated unequivocally that biotoxins such as mycotoxins are associated with a broad range of symptoms, including cognitive decline. These researchers and clinicians identified a constellation of symptoms, signs, genetic predisposition, and laboratory abnormalities characteristic of patients exposed to, and sensitive to, these biotoxins. The resulting syndrome has been designated chronic inflammatory response syndrome (CIRS). The most common cause of CIRS is exposure to mycotoxins, typically associated with molds.

Our findings suggest that patients with presentations compatible with type 3 Alzheimer's disease should be evaluated for CIRS (as well as other toxic exposures, such as mercury and copper). These are treatable etiologic agents, and thus treatable causes of Alzheimer's disease. Furthermore, it may be particularly important to identify or exclude these toxins in patients with type 3 Alzheimer's disease since amyloid may be protective against toxins, especially metals, so reducing the amyloid burden without reducing the toxic exposure may potentially exacerbate the pathophysiology. Conversely, the exclusion of patients with type 3 Alzheimer's disease may potentially enhance the group efficacy of anti-amyloid therapies.

It is noteworthy that there has been direct detection of fungi in the brains of patients who had died with Alzheimer's disease, contrasting with a lack of detection of fungi in control brains. This finding raises the possibility that the mycotoxic effects that occur in CIRS associated with type 3 Alzheimer's disease may be accompanied by active infection. However, unlike in the case of CIRS, there is as yet no indication that treating the putative fungal infection has any ameliorative effect on the cognitive decline. The increasing number of reports of various pathogens identified in the brains of patients with Alzheimer's disease raises the possibility that what is referred to as Alzheimer's disease may actually be the result of a protective response to various brain perturbations. Thus amyloid may function as part of an inflammatory/antimicrobial response.

A Study Suggesting that Dementia Incidence is Declining
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The research noted here stands in opposition to the present consensus on dementia, which is that incidence will increase as other age-related diseases are increasingly controlled. Many people avoid dementia because other conditions kill them first, particularly heart disease. If given additional years of life thanks to improved therapies, then some will later suffer dementia. However, it appears that the improvements in vascular health in old age that have reduced the impact of heart disease also have the effect of significantly reducing dementia incidence. A large fraction of the causes of dementia is a matter damage and dysfunction of the blood vessels in the brain, leading to slow, incremental structural damage to brain tissue.

Despite the concern of an explosion of dementia cases in an aging population over the next few decades, a new study, based on data from the Framingham Heart Study (FHS), suggests that the rate of new cases of dementia actually may be decreasing. It is believed that the number of Americans with Alzheimer's disease and other dementias will grow each year as the size and proportion of the U.S. population age 65 and older continues to increase. By 2025 the number of people age 65 and older with Alzheimer's disease is estimated to reach 7.1 million - a 40 percent increase from the 5.1 million aged 65 and older affected in 2015. By 2050, the number of people in this age population with Alzheimer's disease may nearly triple, from 5.1 million to a projected 13.8 million, barring the development of medical breakthroughs to prevent or cure the disease.

FHS participants have been continuously monitored for the occurrence of cognitive decline and dementia since 1975. Thanks to a rigorous collection of information, FHS researchers have been able to diagnose Alzheimer's disease and other dementias using a consistent set of criteria over the last three decades. Researchers looked at the rate of dementia at any given age and attempted to explain the reason for the decreasing risk of dementia over a period of almost 40 years by considering risk factors such as education, smoking, blood pressure and medical conditions including diabetes, high blood pressure or high cholesterol among many others.

Looking at four distinct periods in the late 1970s, late 1980s, 1990s and 2000s, the researchers found that there was a progressive decline in incidence of dementia at a given age, with an average reduction of 20 percent per decade since the 1970s, when data was first collected. The decline was more pronounced with a subtype of dementia caused by vascular diseases, such as stroke. There also was a decreasing impact of heart diseases, which suggests the importance of effective stroke treatment and prevention of heart disease. Interestingly, the decline in dementia incidence was observed only in persons with high school education and above.


Long-Term Benefits of Senolytic Drugs on Vascular Health
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Senolytic treatments are those that at least partially clear senescent cells, producing a narrow form of rejuvenation, enhanced longevity, and improvement in long-term health. One of the fortuitous discoveries of recent years was that a combination of the drugs dasatinib and quercetin can clear enough senescent cells in a single treatment in mice to demonstrate that doing so is beneficial. The research noted here extends that result to investigate some of the outcomes of a series of treatments over time.

It is unfortunately unlikely that the same degree of clearance will happen in humans via the use of these particular drugs, but people are certainly going to try anyway. The real value of this research lies in the ability to prove that getting rid of these cells is robustly beneficial in mammals. This will result in increased support for the clinical development of methods that will work in humans. Some of those methods already exist in prototype form and work is presently underway on these approaches at Oisin Biotechnology and Unity Biotechnology, for example.

Cells become senescent in response to stress or damage, irreversibly removing themselves from the cycle of division and replication. This most likely initially serves to reduce risk of cancer by suppressing the ability of the most vulnerable cells to become cancerous, but as the number of senescent cells rises, they have a growing detrimental effect on tissue function. Senescent cells secrete signals that produce chronic inflammation, haphazardly remodel surrounding tissue structures, and encourage bad behavior in neighboring cells. In short, senescent cells are one of the causes of aging, and therapies under development to remove them are the first practical rejuvenation biotechnologies after the SENS model.

Building on previous studies, researchers have demonstrated significant health improvements in the vascular system of mice following repeated treatments to remove senescent cells. They say this is the first study to show that regular and continual clearance of senescent cells improves age-related vascular conditions - and that the method may be a viable approach to reduce cardiovascular disease and death. "Cardiovascular disease remains the leading cause of death in our population today, and disability related to heart disease and stroke has a tremendous impact on our aging population. This is the first evidence that longer term use of senolytic drugs to clear these damaged cells from the body can have a preventative impact against vascular diseases."

Senescent cells are damaged cells that no longer function properly, but remain in the body and contribute to frailty and many of the other health conditions associated with aging. Prior studies showed chronic removal of the cells from genetically-altered mice can alter or delay many of these conditions, and short-term treatment with drugs that remove senescent cells can improve the function of the endothelial cells that line the blood vessels. This study, however, looked at the structural and functional impacts of cell clearance using a unique combination of drugs on blood vessels over time. Mice were 24 months old when the drugs - a cocktail of dasatinib and quercetin - were administered orally over a three-month period following those initial two years. A separate set of mice with high cholesterol was allowed to develop atherosclerotic plaques for 4 months and were then treated with the drug cocktail for two months.

The research showed that senescent cell clearance in either naturally-aged or atherosclerotic mice alleviated vascular dysfunction. Although it did not reduce the size of plaques in mice with high cholesterol, it did reduce calcification of existing plaques on the interior of vessel walls. "Our finding that senolytic drugs can reduce cardiovascular calcification is very exciting, since blood vessels with calcified plaques are notoriously difficult to reduce in size, and patients with heart valve calcification currently do not have any treatment options other than surgery. While more research is needed, our findings are encouraging that one day removal of senescent cells in humans may be used as a complementary therapy along with traditional management of risk factors to reduce surgery, disability, or death resulting from cardiovascular disease."


Arguing that Progeria Mechanisms are Significant Enough in Normal Aging to Be Worth Addressing
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Today I'll point out a very long post that argues we should pay more attention to the mechanisms of Hutchinson-Gilford progeria syndrome (HGPS, or simply progeria) in normal aging. Progeria is one of a small number of rare conditions in which patients have the appearance of accelerated aging. It isn't really accelerated aging, but it is at root a form of biological breakage that leads to greatly increased rates of cellular damage and dysfunction. This produces medical conditions that overlap with those of normal aging since they, also, are the consequence of high levels of cellular damage and dysfunction. Both aging and progeria result in cardiovascular disease and kidney failure, for example, but the root causes are very different. In the case of progeria damage results from a mutation in the lamin A gene, and as a consequence an encoded protein that is vital to cellular function has abnormal behavior. Among other issues observed in progeroid tissues, cell nuclei are misshapen and the ability for cells to replicate is consequently limited.

The cause of progeria was discovered not so long after the turn of the century, and researchers have since then made some inroads towards a treatment. The latest and most promising - and perhaps also the most surprising - is the use of methylene blue, one of the oldest of modern medical compounds. Along the way, evidence has accumulated for the basic mechanism of progeria, damaged lamin A, to be present to a small degree in normally aged tissues. It is far from clear that this has any meaningful impact in comparison to the other forms of cell and tissue damage that cause aging, and for my part I would be surprised to find that it rivals the others to a level that demands action now. This is still a scientific discussion in progress, however, and opinions can differ.

The post linked here is written from a programmed aging perspective, which I think tends to make people look for links that are not there. In search of a genetic program for degenerative aging, the author proposes that lamin A mutations can act as a trigger for that program, and therefore it is worth following the chain of cause and consequence to see what falls out of that investigation. In the alternative view of aging as the consequence of accumulated damage, there is no need for such work: damage causes dysfunction, and progeria is just a much more uniform source of fundamental cellular damage than is the normal aging process. Our level of concern with progeria should therefore match the degree that it contributes to normal aging, which is at present an open question with the presumption that the answer will probably be "not greatly."

Hutchinson-Gilford Progeria Syndrome - a disease of accelerated aging due to Alternative Splicing

HGPS has received attention because it so closely mimics the normal picture of aging. A main difference between normal aging and HGPS is that the entire "aging program" is completed in about 15 years with HGPS, whereas with normal aging, the "aging program" takes almost 100 years to complete. Whereas a few people with normal aging can live as long as 122 years, almost all of the people with HGPS die by 16-20 years of age. The most common findings in HGPS include features that mimic normal aging, such as alopecia, skin atrophy, mottled pigmentation of the skin, generalized lipodystrophy, joint stiffness, arthritis, arteriosclerosis, coronary artery disease, left ventricular enlargement, and strokes. However, HGPS children also have unique findings that do not "mimic" normal aging, such as absent eyebrows, prominent eyes/proptosis, micrognathia, open cranial bone fontanelles, and absent sexual maturation. This is why some have called HGPS a "caricature of normal aging", rather than a "copy of normal aging."

Until 2006, no one really thought that there was much true overlap between HGPS and normal aging. Even expert scientists studying the biology of aging did not think that progerin, the mutant form of prelamin A, accumulated in cells undergoing normal aging. No one says that today. Several independent research teams have published data between 2006 and 2013 which confirm that progerin accumulates in normal skin cells with aging and triggers the same cellular and molecular features of HGPS. Another recent study showed that cellular senescence induces progerin production, whereas immortalized cells suppressed progerin production. Further, progerin accumulates as a function of chronological aging in the blood vessel walls of normal individuals who do not have HGPS. Although the adventitia has the highest concentration of progerin, it also accumulates in the media and intima as well. Progerin accumulation in the walls of blood vessels only affects 1 out of every 1,000 cells at birth and increases at a rate of 3.34% per year. As the endothelial cells divide, they "pass on" the progerin to subsequent generations of daughter cells.

The first obvious lesson we can learn from HGPS is that "a single gene abnormality can trigger the entire aging program". This is not to say that aging is simply due to a cryptic space site mutation in the LMNA gene, but rather that one cryptic splice site can trigger all of aging. HGPS is not the only disease that can do this. Several other diseases due to single point mutations in completely different genes can do the same thing (Ex: DNA repair deficiencies such as Werner's syndrome). However none of these other mutations produce an "aging phenotype" at such a young age or that has such a close resemblance to normal aging. For instance, Werner's syndrome does produce an accelerated aging phenotype that looks like normal aging, but occurs later in life (This is why Werner's syndrome is often called "adult progeria").

Another important lesson we can learn from HGPS is that this disease shows that aging is more like a program which is accelerated from the normal 100 years (normal aging) to 15 years (HGPS). Nature has given us many examples of "molecular programs", such as gestation and embryogenesis. It is hard for most people to accept that aging is programmed too, but there is good evidence for this. The best line of evidence against a non-programmed type of aging is that 100% of humans develop the same set of features with aging in a similar order of events. If aging was truly a random, stochastic event, the features of aging would occur in random order and would not affect 100% of human beings (i.e. random events don't happen 100% of the time in the same order). The fact that over 80% of the features of normal aging are also seen in children with HGPS suggest that this disease is truly an accelerated aging model. The million dollar question, however, is can this aging program be reversed or slowed?

Needless to say I don't agree with any of the above thinking on programmed aging and the relevance of progeria in that light. The ordering argument doesn't seem a good one to me: people do develop age-related conditions in different orders, and the overall progression of aging is the gestalt of countless trillions of molecular events, meaning that randomness is smoothed over time. The author does present and comment on a great many papers on the molecular biochemistry of progeria and aging, and the post is well worth reading for that regardless of where you stand on aging as a process.

Tuning Macrophages in Cancer Immunotherapy
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Immunotherapy is a broad category, and covers many very different strategies for tackling cancer and other conditions by engineering immune cells or adjusting the behavior of the immune system as a whole. In this case, researchers have found a novel and interesting approach:

Similar to stem cells differentiating to make your body's tissues, the immune system's macrophages pick a life path, differentiating into macrophages that recruit resources for wound repair or macrophages that recruit resources for wound sterilization. Cancers encourage macrophages to pick the path of wound-repair, making what are called "M2" or "repair-type" macrophages. Cancers use these M2 macrophages to promote their own growth. However, researchers can now successfully flip M2 macrophages into their wound-sterilizing cousins, called "M1" or "kill-type" macrophages, which, contrary to promoting the growth of new tissue, may aid the immune system in clearing the body of cancer.

Previous work has shown that people with a naturally high ratio of M1 to M2 macrophages are less prone to develop cancer. And in mouse models of the disease, encouraging a high M1-to-M2 ratio can "slow or stop cancer growth." In fact, there are two schools of thought describing how, exactly, to change a population of M2 macrophages into a population of M1 macrophages. In the first school of thought, M2 macrophages can reverse their differentiation to become briefly more "stem-like" before being encouraged to use their second chance to pick the more beneficial M1/kill-type phenotype. In the second school of thought, as macrophages naturally die out, they could be replaced by a new population dominated by M1 macrophages. The paper describes a way to accomplish the second: In the presence of the cytokine interferon gamma, macrophages take on the M1 phenotype.

"Interferon gamma has been explored as a possible therapeutic agent, but there are problems with it. Interferon gamma mediates hundreds of effects and some of them aren't very comfortable." Instead, one idea is to improve the sensitivity of cells to the interferon gamma that already exists in the body. "In the right context, macrophages lose their sensitivity to interferon gamma and we want to prevent that." Another approach seeks to augment interferon gamma only in tumor tissue, keeping its effects localized. "The immune system's killer cells produce interferon gamma and one promising strategy is to get them to the tumor and activated in the right way." In fact, existing immunotherapies seek to recruit the body's killer cells, especially cytotoxic T cells, to recognize and attack tumor tissue. A byproduct of this activation is the production of interferon gamma at the tumor site, which causes macrophages to take the M1 and not M2 phenotype. "Cytotoxic T cells can directly kill tumor cells. But they also produce interferon gamma. Both are likely contributing to the anti-tumor effect. By devising approaches to tune macrophages in the right way, we hope to further improve immunotherapies."


On Building Measures to Link Aging and Disease
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In this popular science article on the relationship between aging and age-related disease, a researcher discusses one of a number of approaches to producing a biomarker of aging, a sensitive measure of the degree to which an individual is impacted by the cell and tissue damage of aging. A good biomarker should predict the onset of disease and remaining life expectancy to the degree that these are determined by damage:

In epidemiological studies, particular those focused on the molecular mechanisms of 'growing older', loss of function and the emergence of 'biomarkers' of disease, even in young middle-aged 'healthy' adults, are often presented as diagnostics for human ageing. From my perspective, this is almost certainly misleading as it implies that health, disease and longevity are all interchangeable synonyms for ageing. If we wish to identify a definitive 'ageing' molecular programme (e.g. biological age), one that is independently informative for future health and life span then it is critical that we clearly define what is meant by the term 'ageing' and appropriately develop an assay that measures this parameter. We also have to consider if the developed diagnostic, while statistically significantly related to biological age, is sufficiently sensitive and specific enough to be considered a useful diagnostic (most will fail this final criteria e.g. telomere assays).

The other major consideration relates to how a novel diagnostic of 'biological age' would be used. If it were to be used as an independent diagnostic of longevity then it would be combined with other factors and behaviours that determine life-span, such as smoking and obesity. One could imagine the generation of an integrated risk 'score' utilised to determine insurance premiums for healthcare or to calculate pension requirements. These may seem controversial examples, but in reality our chronological age (birth year) and behaviours are already judged and used for these purposes. Why not have a more accurate 'diagnosis' of the contribution 'age' makes to these decisions? For example, if you are a poor 'biological age' (for your chronological age) then your breast-cancer or prostate-cancer screening might be scheduled 5-10 yr earlier than average.

Variation in the human transcriptome (RNA) has proven particularly powerful for identifying the huge variations in human physiology and physiological responses to environmental influences. So it is not surprising it has been used to develop diagnostics of human ageing, including our own model. While you can't use chronological age to diagnose the health status of an individual - the relationship between chronological age and disease is an epidemiological one - existing RNA or DNA methylation assays represent composites of ageing, disease and drug-treatment and not chronological age. We believe that 'biological' age will determine when you show clinical symptoms of disease and that we need an assay which accurately reflects your underlying 'rate of ageing' or 'biological age'. Which 'age associated' disease an individual then develops will depend on their genetic, epigenetic and environmental risks factors (and stochasticity).

To produce this new diagnostic of 'biological age' we had the hypothesis that we can find a set of RNAs in the tissue that was diagnostic for telling tissue from healthy old from healthy young people apart. In our study healthy old people were living a normal sedentary lifestyle, did not have type II diabetes and importantly had good fitness levels. By applying machine learning to this 'special' healthy ageing cohort, we found 150 RNA markers. In fact we could see that these 150 RNAs were either up or down regulated in tissue from healthy old people and we reasoned that activation of this gene expression 'programme' may help explain why these 65 year old people achieved good health despite living a sedentary life style. In fact, when we then applied the 150 RNA assay to a group of 70 year old people (people with the same chronological age) we found that their 'biological age' score varied dramatically and for those that failed to switch the gene expression pattern "on" as much died sooner and had a greater decline in organ function (kidney).


21st Century Medicine Wins the Small Mammal Brain Preservation Prize
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The folk at 21st Century Medicine have been working, largely unheralded, for years with the aim of improving the technologies used in cryopreservation of tissue. The goals are twofold: firstly to make cryonics a much more reliable and robust end of life choice, and secondly to introduce reversible organ vitrification into the tissue engineering and transplant industry. These go hand in hand, as if it is possible to store a kidney for years or decades and later transplant it, fully functional, into a patient, then it is also possible for the body and brain to be preserved at death rather than going to the grave and oblivion. This opens up the chance at a longer life in the future for those who will age to death too soon to benefit from the rejuvenation therapies presently under development.

Cryonics, like longevity science, is simultaneously one of the most neglected and important areas of science and development. So very many lives could be saved were there just a little more support for the growth of this industry. So I am pleased to see that the 21st Century Medicine researchers have won the Small Mammal Brain Preservation Prize offered by the Brain Preservation Foundation. They have demonstrated exceptional preservation of the fine structures of the brain that the present scientific consensus believes store the data of the mind. This is an important step forward for cryonics, being both the basis for a potentially better approach to cryopreservation, as well as solid support for the contention that cryopreservation of the brain preserves the mind. This is good, unequivocal evidence to add to that from last year's study demonstrating that memory survives vitrification in nematode worms.

Newly invented Aldehyde-Stabilized Cryopreservation procedure wins Brain Preservation Prize

The Small Mammal Brain Preservation Prize has officially been won by researchers at 21st Century Medicine. Using a combination of ultrafast chemical fixation and cryogenic storage, it is the first demonstration that near­ perfect, long­-term structural preservation of an intact mammalian brain is achievable. You can view images and videos demonstrating the quality of the preservation method for yourself at the evaluation page. This result directly answers what has been a main scientific criticism against cryonics, and sets the stage for renewed interest, research, and debate within the mainstream scientific and medical communities. "​Every neuron and synapse looks beautifully preserved across the entire brain. Simply amazing given that I held in my hand this very same brain when it was vitrified glassy solid... This is not your father's cryonics."

A team from 21st Century Medicine, spearheaded by recent MIT graduate Robert McIntyre, has discovered a way to preserve the delicate neural circuits of an intact rabbit brain for extremely long-­term storage using a combination of chemical fixation and cryogenic cooling. Proof of this accomplishment, and the full "Aldehyde ­Stabilized Cryopreservation" protocol, was recently published in the journal Cryobiology and has been independently verified by the Brain Preservation Foundation through extensive electron microscopic examination.

Throughout the contest, the 21CM team was in a tight race with Max Planck researcher Shawn Mikula to be the first to meet the prize's strict requirements. Although the prize will be awarded to 21CM, we wish to emphasize that a mouse brain entry submitted by Dr. Mikula also came extremely close to meeting the prize requirements. Dr. Mikula's laboratory is attempting to perfect not only brain preservation (using a different method based on chemical fixation and plastic embedding) but whole brain electron microscopic imaging as well. Focus now shifts to the final Large Mammal phase of the contest which requires an intact pig brain to be preserved with similar fidelity in a manner that could be directly adapted to terminal patients in a hospital setting. The 21st Century Medicine team has recently submitted to the BPF such a preserved pig brain for official evaluation. Lead researcher Robert McIntyre has started the company Nectome to further develop this method.

Aldehyde-stabilized cryopreservation

We describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. ASC is a new brain-banking technique designed to facilitate neuroanatomic research such as connectomics research, and has the unique ability to combine stable long term ice-free sample storage with excellent anatomical resolution. To demonstrate the feasibility of ASC, we perfuse-fixed rabbit and pig brains with a glutaraldehyde-based fixative, then slowly perfused increasing concentrations of ethylene glycol over several hours in a manner similar to techniques used for whole organ cryopreservation. Once 65% w/v ethylene glycol was reached, we vitrified brains at -135C for indefinite long-term storage.

Vitrified brains were rewarmed and the cryoprotectant removed either by perfusion or gradual diffusion from brain slices. We evaluated ASC-processed brains by electron microscopy of multiple regions across the whole brain and by Focused Ion Beam Milling and Scanning Electron Microscopy (FIB-SEM) imaging of selected brain volumes. Preservation was uniformly excellent: processes were easily traceable and synapses were crisp in both species. Aldehyde-stabilized cryopreservation has many advantages over other brain-banking techniques: chemicals are delivered via perfusion, which enables easy scaling to brains of any size; vitrification ensures that the ultrastructure of the brain will not degrade even over very long storage times; and the cryoprotectant can be removed, yielding a perfusable aldehyde-preserved brain which is suitable for a wide variety of brain assays.

One interesting point worth noting is that many of the people involved in these efforts don't see restoration as the ultimate goal of cryonics. Rather they are in favor of scanning the structure of the brain, possibly destructively, followed by reconstruction of the mind in software in the form of a whole brain emulation of some sort. So to their eyes the complete goal here is fidelity of preservation, the quality of the vitrification of fine structures: everything else is a matter of scaling up the capabilities of scanning, software, and computational hardware, all of which look like foregone conclusions for the decades ahead at the moment. For those of us who think that a copy of the self is someone else, and for whom the self means the actual physical structure of the brain, there is the matter of how this preservation would be reversed in the future, however. It is very interesting - and encouraging - to watch progress towards reversible vitrification of organs for the transplant and tissue engineering industry, as that is where the still missing pieces of technology needed for the other side of cryonics will emerge.

In Search of the Genetics of Longevity in Sea Urchins
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Comparative biology is an important tool in aging research, as the analysis of similar species with widely divergent life spans can in theory point out the more important mechanisms of aging. The more similar the species the better, and so here researchers investigate the genetics of two sea urchin species that exhibit a twenty-fold difference in life span. This is a preliminary set of data, absent any rigorous analysis, but even at the outset it doesn't exactly fit the expected picture. There is no real reason to expect a universality of relative importance of mechanisms across diverse species, so things that have proved to be important in well-studied species such as flies, mice, and people may well turn out to have little relevance to more distant branches of the tree of life. As a general rule, we should always expect biology to be more complex and varied rather than less so:

Sea urchins have attracted attention due to the extreme longevity of some of their species. Red sea urchin, S. franciscanus, populating cold waters of Pacific coast of North America, was demonstrated to survive over a century. Although S. franciscanus could not be cultivated in the lab for a century for direct observation, deposition pattern of radioactive carbon released to the Pacific upon nuclear tests and skeleton growth rate studies using tetracycline labeling allowed red sea urchin to climb the pedestal of the most long-lived marine animals. At the same time, green sea urchin, L. variegatus, populating warm Caribbean sea hardly survive over four years. Although direct difference in the senescence rates between red and green sea urchins is hard to demonstrate directly on the sole basis of field studies, these two related species might be the a convenient pair for comparative genetics of longevity. In this report we aimed to obtain draft genome assemblies of S. franciscanus and L. variegatus and compare the sequence of their proteins related to longevity with longevity related proteins of other species.

Analysis revealed several aminoacid positions that co-vary with longevity. Although this approach is not guaranteed from mistakes originated from misalignment, identification of related proteins that have different function, it could present a framework of further hypothesis-driven experiments on longevity. Our analysis revealed highly uneven distribution of proteins having aminoacid residues that co-vary with longevity among functional categories. Surprisingly, several categories of proteins were completely devoid of such positions. For example, nuclear encoded mitochondrial proteins and proteins involved in reactive oxygen species inactivation. Minimum of such aminoacids were found in the components of insulin/IGF1 pathway. Particularly enriched in positions that vary in coordination with longevity are categories of mitochondrial proteins encoded in mitochondrial genome, lipid transport proteins, proteins involved in amyloidogenesis and system of telomere maintenance. Among other, catalytic subunit of telomerase, telomerase reverse transcriptase (TERT) holds absolute record of the frequency of such positions. Despite the fact, that somatic telomerase activity could be detected in short and long living sea urchins, TERT might be involved in longevity due to more intricate mechanisms, such as maintaining the balance between support of tissue renovation and simultaneous restriction of unwanted proliferation of cancerous cells.


Protecting Osteoblasts to Enhance Bone Mass and Strength
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Bone is constantly remodeled at the small scale, created by cells called osteoblasts and destroyed by cells called osteoclasts. One of the proximate causes of osteoporosis, age-related loss of bone mass and strength, is a growing imbalance between these two cell populations. Any of a range of approaches that can tilt the balance back towards osteoblasts and bone creation is likely to slow skeletal degeneration, and that is demonstrated in mice in the study linked here. As a matter of interest note that this particular approach is the exact opposite of that used in the first senolytic drugs: inhibiting cell self-destruction rather than encouraging it via the same target of Bcl2 proteins.

The Bcl2 family proteins, Bcl2 and BclXL, suppress apoptosis by preventing the release of caspase activators from mitochondria through the inhibition of Bax subfamily proteins. We reported that BCL2 overexpression in osteoblasts increased osteoblast proliferation, failed to reduce osteoblast apoptosis, inhibited osteoblast maturation, and reduced the number of osteocyte processes, leading to massive osteocyte death. We generated BCLXL transgenic mice using the same promoter in order to investigate BCLXL functions in bone development and maintenance.

Bone mineral density in the trabecular bone of femurs was increased, whereas that in the cortical bone was similar to that in wild-type mice. Osteocyte process formation was unaffected and bone structures were similar to those in wild-type mice. A micro-CT analysis showed that trabecular bone volume in femurs and vertebrae and the cortical thickness of femurs were increased. Analysis revealed that the mineralizing surface was larger in trabecular bone, while the bone formation rate was increased in cortical bone. The three-point bending test indicated that femurs were stronger in BCLXL transgenic mice than in wild-type mice.

The frequency of TUNEL-positive primary osteoblasts was lower in BCLXL transgenic mice than in wild-type mice during cultivation, and osteoblast differentiation was enhanced, but depended on cell density, indicating that enhanced differentiation was mainly due to reduced apoptosis. Increased trabecular and cortical bone volumes were maintained during aging in male and female mice. These results indicate that BCLXL overexpression in osteoblasts increased the trabecular and cortical bone volumes with normal structures and maintained them majorly by preventing osteoblast apoptosis, implicating BCLXL as a therapeutic target of osteoporosis.


Is the Present Human Life Span Enough?
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Is the present human life span enough? This was the topic for a recent debate, wherein Aubrey de Grey of the SENS Research Foundation and Brian Kennedy of the Buck Institute were matched against Ian Ground of Newcastle University and Paul Root Wolpe of the Emory Center for Ethics. Obviously my answer to the question is a resounding no; we should absolutely be doing far more than we are to eliminate aging and extend healthy life spans to the greatest degree possible. I am in a minority for holding that view, however. A growing minority, but a minority nonetheless. Two thirds of the population, when asked, say that yes, the present length of life is just fine. For my money, I think this is simply that most people live in the moment, within the bounds of what is, and give little thought to what might be different. If the wall is white and has always been white, you'll only get blank stares if you ask people what color it should be. What is familiar is equated with what is best, or sufficient, or good. Most people see the future as more of the present, just a different day with different fashions. Managing to hold this state of mind whilst standing amidst the fastest pace of progress in history is a feat, but clearly we humans are up to it.

Perhaps the most interesting aspect of the position that present length of life is sufficient is that near all of the people who think this way, will if asked, also say that cancer, heart disease, Alzheimer's, and other well-known age-related conditions should be cured. This is inconsistent, to say the least, as these conditions are caused by aging. They, and the other failure modes of organs and tissues that have been given formal names, are what kill people. Aging is the wear and tear that gives rise to these conditions, but these are not separate things. The only way to prevent age-related disease is to control the processes of aging - such as through periodic repair of damage after the SENS model - so as to indefinitely sustain function and health. If function and health are sustained, then life is lengthened. It is impossible to decouple aging from health.

The next time you find someone who thinks that the present length of life is fine, ask them what disease they want to suffer and die from. What is an acceptable way to decay into death? Heart disease? Kidney failure? How about neurodegeneration, the loss of the mind? My guess is that they don't want to suffer any of the above, and have hazy notions of an easy death at the end of life. Modern societies have pushed the ugly realities of what it means to age to death out of mind, behind curtains and into nursing homes and hospitals. That ugly reality for near everyone is pain and degeneration, the loss of function over time, and a very unpleasant end. Again, the only way to prevent that is to control the underlying processes of damage that cause aging and disease, and by doing so extend health and life. There is no picking that apart. It is only through ignorance of how things actually work in our biology that people can hold the strange and inconsistent positions that they do on aging, medicine, and longevity.

Lifespans are Long Enough

What if we didn't have to grow old and die? The average American can expect to live for 78.8 years, an improvement over the days before clean water and vaccines, when life expectancy was closer to 50, but still not long enough for most of us. So researchers around the world have been working on arresting the process of aging through biotechnology and finding cures to diseases like Alzheimer's and cancer. What are the ethical and social consequences of radically increasing lifespans? Should we accept a "natural" end, or should we find a cure to aging?

Is 78.8 Years Long Enough to Live?

First to argue in favor of the motion that "Lifespans are long enough" was professor of bioethics and director of the Emory Center for Ethics, Paul Root Wolpe. He said: "We all want to live longer. Maybe even forever. But I think the quest for immortality is a narcissistic fantasy. It's about us. It's about me. It's not about what's good for society." As Wolpe saw it, the question is not about whether it's possible to extend life but whether it's desirable. He viewed making the pursuit of indefinitely long life a goal in and of itself as wrong-headed. "Will life extension make the world a better place, a kinder place? Has extended life expectancy made it better? I don't think so," Wolpe said.

First to debate against the motion that lifespans are long enough was Aubrey de Grey, chief science officer of SENS Research Foundation. "I believe that the defeat of aging is the most important challenge facing humanity," he declared. "I'm going to start with this question about the alleged conflict between individual desire and societal good." De Grey compared the issue to people not wanting themselves or anyone else to get Alzheimer's disease. "It's a societal good because we don't like each other to get sick any more than we want to get sick," he said. De Grey doesn't believe that future problems are anywhere near as horrifying as the problem we have today. He said: "Let me tell you exactly how bad the problem that we have today actually is. Worldwide roughly 150- to 160,000 people die each day. And more than two-thirds of those people die of aging. It's crazy. In the industrialized world, we're talking more like 90 percent of all deaths. Let's actually do something about it."

Philosopher Ian Ground of Newcastle University and Secretary of the British Wittgenstein Society supported the motion that lifespans are long enough. Ground questioned the wisdom of having an indefinitely long life that could be led with no thought about its ending or decline. He urged us to consider a decision like committing to a certain career, person or place. People can't do everything, marry everybody or live everywhere, Ground said. We become particular people by making those choices, and must recognize that with natural capacities come natural limitations, he added.

The final panelist, who argued against the motion "Lifespans Are Long Enough," was Brian Kennedy, CEO and president of the Buck Institute for Research on Aging. Kennedy addressed speculation from the previous three speakers about what life might be like if we lived to 150, from how society would change to the prospect of boredom. "Maybe we're going to be bored. Well, you know, if you ask me: 'Do I want to have cancer at 75? Do I want to have Alzheimer's disease at 85? Or do I want to be bored at 110?' I know which one I'm going to take," said Kennedy.

In the end, the team arguing against the motion "Lifespans Are Long Enough" won, according to the audience. The post-debate score results were 40 percent for the proposition, 49 percent against and 11 percent undecided.

Aging Hair Follicles Change to Become Skin
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An interesting mechanism that appears to contribute to age-related hair loss was recently identified. It is unusual in that cells of one tissue structure are changing to cells of another as a result of age-related damage:

Scientists have uncovered a new mechanism behind hair loss: When stem cells in hair follicles are damaged by age, they turn themselves into skin. Over time, this happens to more and more stem cells, causing hair follicles to shrink and eventually disappear. This is the first time such a switch has been associated with aging in any tissue. Stem cells - precursor cells that can give rise to specialized cells like skin and hair - regenerate throughout the life of an organism and are located all over the body. But unlike stem cells in the blood or intestinal lining, hair follicle stem cells regenerate on a cyclical basis. Their active growth phase is followed by a dormant phase, in which they stop producing hair. These discrete on-off periods make hair follicle stem cells a useful model for studying stem cell regulation - and hair loss.

To figure out why hair thins in old age, researchers looked at hair follicle stem cell growth cycles in live animals - a daunting task - and found that age-related DNA damage triggers the destruction of a protein called Collagen 17A1. That in turn triggers the transformation of stem cells into epidermal keratinocytes. In their new state, the damaged stem cells slough off easily from the skin's surface. "When damaged cells deplete that niche of collagen 17A1, they alter their own signaling environment. It is interesting that these damaged cells change their fate rather than committing suicide through apoptosis (programmed cell death) or stopping cell division through senescence."

To see whether their results carried over to people, the researchers analyzed hair follicles in scalps from women aged 22 to 70. They found that follicles in people over 55 were smaller, with lower levels of Collagen 17A1. "We assume that ... aging processes and mechanisms similar to those in the mice explain the human age-associated hair thinning and hair loss." Stem cell depletion is unlikely to be the only factor behind the condition, however.


How Do Stem Cell Transplants Produce Heart Regeneration?
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Stem cell transplants spur greater regeneration in an injured heart that would normally be the case, and so far it appears to be the case that this is a matter of signaling that changes the behavior of native cells rather than the transplanted stem cells integrating with native tissue and generating new cells. Past studies have shown that the stem cells don't last long following transplant. Nonetheless the beneficial effects do last quite a while, and this is presently a mystery - what mechanisms are mediating this result? This is the latest in a line of studies that examine this question, and the novel finding here is that the transplanted cells do leave behind a lingering population of new cells in the heart, but the nature of those cells is unexpected, which is perhaps why past studies have missed them:

In numerous clinical trials, researchers have injected patients with various types of progenitor cells to help heal injured hearts. In some cases, subjects have ended up with better cardiac function, but exactly how has been a subject of disagreement among scientists. According to study on rats, the introduced cells themselves don't do the job by proliferating to create new muscle. "These cells do not become adult cardiac myocytes. So the mechanism is clearly a paracrine action, where the cells release 'something' which makes the heart better. And the million-dollar question now is, 'What is the something?'"

Researchers investigated the fate of so-called c-kit+ cells, progenitors harvested from the heart and named for the presence of a particular kinase. These cells have been the source of a long debate about their role in building cardiac muscle, with some studies finding no evidence of them producing new cardiomyocytes in vivo and others concluding that, if the conditions are right, c-kit cells do indeed make heart muscle. C-kit cells have also been deployed in a clinical trial on heart attack patients. Studies on a variety of cardiac cell therapies have found that the vast majority of the cells don't stick around in the heart for much longer than a few weeks, suggesting that their mode of action is likely not based on the cells themselves producing new muscle tissue directly. To test whether that's the case with c-kit cells, researchers harvested c-kit cells from healthy male rats' hearts and injected them into female rats who had been made to have a heart attack.

Compared to controls, the treated rats had smaller scars, more muscle in their hearts, and improvements in cardiac function. To follow what had happened to the injected c-kit cells, the researchers picked out cells with Y chromosomes, finding that they made up 4 percent to 8 percent of the nuclei in the heart. Many of them had lost c-kit positivity, and it was clear from their morphology that these cells are not heart muscle and don't contribute to cardiac contraction. "Honestly, I do not know what they are. That's what we're trying to figure out." It appeared that the treated animals did have more cell proliferation, which researchers attributes to the cell therapy. "Pretty amazingly, it lasts up to 12 months after transplantation, which is another thing I cannot explain. How can the transplantation, done only once, stimulate a proliferative response for 12 months?"


The SENS Rejuvenation Biotechnology Companies
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After the laboratory, the next stage of development in rejuvenation therapies involves the founding of biotechnology startups. There is no clear-cut point at which research stops being non-profit in the laboratory and starts being for-profit in a venture-funded startup. Every research team eyeballs the time and cost needed to get to the next level, something ready for the first human trial. Once that comes down to a gap that can be crossed with the combination of a seed round and angel investment round - say half a million to a million dollars and a year or two of work with a couple of clearly identifiable goals and go/no-go decisions - then the adventurous will make the leap. As I'm sure you've noticed it looks like a bear market is getting underway, but what better time to pull in investment for a project that might take a couple of years of heads-down work out of the limelight to reach the next stage? Bear markets only last a year or two, so by the time a new biotech startup has completed its first stage work successfully, it'll be ready to catch the headwinds of the next bull market.

Numerous lines of SENS rejuvenation research are, piece by piece, leaving the laboratory for the startup world. This is the success that we as a community have achieved with our years of charitable support for research aimed at advancing the state of the art. Whenever a new SENS-related biotechnology startup launches, bear in mind that a diverse group of people, investors and researchers, have looked at the technology and said "yes, we think can get a prototype therapy for human trials done in a couple of years." It is an important sign of progress, and one that is hard to fake: people with meaningful amounts of money on the line made those calls. You should expect our community to transition in part from one of fellow traveler non-profits and research groups to one made up equally of a network of startups, entrepreneurs, and investors of various stripes, from occasional angels to professionals at venture funds.

Here is a short list of interesting companies I am aware of that are working on SENS-related therapies at various stages, some very new, some years old, and proceeding at differing paces and with different strategies for development. They are not the only companies of interest to people who follow this space: I am omitting Arigos Biomedical, Organovo, and BioViva, among others, but the companies I list below are all very clearly working on aspects of SENS rejuvenation biotechnology. I'm certain there are others that I don't know about at this point - I am certainly far from well connected. I foresee a future in which in addition to the important work still ongoing in the laboratory, we can help to support a incubator-like environment of friendly companies under the SENS umbrella, helping one another succeed, each focused on one slice of the rejuvenation therapies needed to bring an end to aging. Those that succeed will act as guides for the growth of others: in diversity there is the greater chance of finding winning strategies. Importantly, among these companies today there are lot of people who are in this primarily to get the therapies built and out there and available. They are long-term SENS supporters. If they strike it rich, a good portion of that wealth is going to be reinvested in the next cycle of research development because, like us, they have a good idea of which of the two of life and money is more important. That is what success will look like once things become more commercial.


I've posted on the topic of Gensight in the past. This is a French company with tens of millions in venture funding that is built on technology for allotopic expression of mitochondrial genes originally partly funded by the SENS Research Foundation. They are focused on generating a robust commercial implementation for one mitochondrial gene, initially to deploy gene therapies to treat hereditary mitochondrial disease. Creating such a robust implementation is an important foundation for a future effort in which all mitochondrial genes can be backed up to the cell nucleus, and thus the contribution of mitochondrial DNA damage to aging can be eliminated.

Human Rejuvenation Technologies

Human Rejuvenation Technologies is a venture run by philanthropist Jason Hope, who you may recall funded a sizable chunk of the ongoing work on glucosepane cross-link breaking at the SENS Research Foundation back a few years ago. Glucosepane cross-link breaker drug candidates seem to be a few years in the future yet, so Human Rejuvenation Technologies is instead working with a drug candidate for clearing a form of metabolic waste key to plaque formation in atherosclerosis. This candidate is one of the results produced by the long-running SENS Research Foundation LysoSENS program.

Ichor Therapeutics

Ichor Therapeutics has been around for a couple of years, and has done a good job in setting a sustainable lab business on the side. The interesting work here, however, is the continuation of SENS research programs aimed at removing the buildup of A2E, one of the components of lipofuscin that builds up in cells and interferes with cellular garbage disposal. Unusually among the forms of cellular damage, even those involving buildup of metabolic waste such as lipofusin, A2E is linked very directly and solidly to some forms of age-related disease that involve retinal degeneration. In most cases the fundamental damage that causes aging is separated from the end stage of disease by lengthy and barely understood chains of cause and consequence, but here it is very clear that getting rid of A2E is a good thing.

Oisin Biotechnology

Oisin Biotechnology are developing a senescent cell clearance therapy, an approach to treating aging that has definitely arrived with a splash: there are multiple methods demonstrated in mice, and a number of different groups at the point of launching commercial development efforts. Oisin was funded more than a year ago by the Methuselah Foundation and SENS Research Foundation, and you'll be hearing much more about them in the year ahead, I predict.

Pentraxin Therapeutics

Pentraxin Therapeutics is the oldest and slowest of these companies, founded way back in 2001. The SENS-relevant work started in 2008 or 2009 with a partnership with GlaxoSmithKline to develop a treatment to clear transthyretin amyloid, a form of metabolic waste that builds up with age and is linked to cardiovascular disease, osteoarthritis, and death by heart failure in the oldest human beings. A human trial recently produced very positive results, showing significant clearance of amyloid in patients, and this is consequently probably the furthest advanced of all SENS technologies. Unfortunately it is also the most locked up within the slow regulatory system and a Big Pharma partnership. It is hard to say what is going to happen next here, but don't hold your breath expecting to see anything in the clinic soon.

Unity Biotechnology

Unity Biotechnology has emerged from the first successful efforts to clear senescent cells via gene therapy, back in 2011, as well as ongoing programs such as those of the Campisi laboratory. They have a sizable staff for a startup, good venture backing, and are developing treatments based on these methods, but which will be more suitable for use in human patients. You no doubt saw the full court press in the media put on by the various organizational backers of Unity earlier this week. It is great to see such a large number of people pushing the SENS line of damage repair as the approach to treatment of aging. As more companies reach the point of gaining support from deep pockets in the venture community, we will see more of this media attention for SENS-like rejuvenation therapies.