Fight Aging! Newsletter, May 9th 2016

May 9th 2016

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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  • ABT-737 is Another New Senolytic Drug Candidate, Working via BCL-W, BCL-XL, and Induced Apoptosis
  • Views of the Cost and Time Required to Build an Organ Engineering Industry
  • Inhibition of Mitochondrial Complex I Extends Life in Killifish and Zebrafish
  • Progress in Understanding Plant Longevity is Interesting, But is it in Any Way Relevant?
  • Overfund the Life Insurance Policy that Pays for Your Cryopreservation
  • Latest Headlines from Fight Aging!
    • The Importance of Lysosomes in Aging and Longevity
    • Attempting to Extract Causation from the Correlation Between Retirement Age and Life Expectancy
    • Calorie Restriction Improves Quality of Life in Human Practitioners
    • A Sedentary Lifestyle Correlates with Greater Calcification of Heart Tissue
    • Macrophages Repair Broken Capillaries in the Brain
    • HSP27 Attenuates Cardiac Aging in Mice
    • AUTEN-67 as an Example of an Autophagy-Enhancing Drug Candidate
    • Avoiding Weight Gain Across the Whole Lifespan Correlates with a Lower Mortality Rate
    • Mapping Proteomic Changes with Aging in Rats
    • Lower Levels of Some Ceramides Correlate with Better Cardiovascular Fitness


Senolytic therapies are those that cause senescent cells to die while causing minimal side-effects. Developing methods to selectively destroy senescent cells has been on the SENS rejuvenation research agenda for going on fifteen years, based on strong evidence from many fields, but only recently have factions within the broader research community started to pick up on this approach to treating one of the causes of aging. Over the past two years a tipping point of sorts was reached and passed, and now a number of drug candidates are emerging from research groups, and the startup Oisin Biotechnologies has a more selective gene therapy approach to achieve the same aim. The open access paper I'll point out today describes one of these candidates, along with animal data that shows it destroying between a quarter and a half of senescent cells in a few tissues. This is on a par with the performance of some of the other candidates that have produced improved measures of health in mice.

Why destroy senescent cells? Because they help to make us old. Cells become senescent in response to reaching the Hayflick limit to the number of divisions, or when suffering damage, especially DNA damage likely to produce cancerous mutations, or a toxic local environment that seems likely to produce that sort of damage. Senescent cells cease to replicate and most self-destruct via apoptosis, or are targeted by immune cells for destruction. Some linger however, secreting a problematic mix of signals that induce inflammation and remodeling of tissue structures, while also encouraging neighboring cells to become senescent. As the years pass ever greater numbers of these cells cause ever greater disarray, contributing meaningfully to the development and progression of all common age-related diseases, and ultimately the tissue and organ failures that cause death. If all senescent cells were periodically removed, however, never permitted to assemble in large numbers, then this part of the aging process would be eliminated, the span of healthy life extended, and age-related disease pushed off that much further into the future. This has been demonstrated in a life span study in mice, in which continuous senescent cell removal via genetic engineering produced a 25% extension of median life span.

How to destroy senescent cells? In past years, I predicted that targeted therapies like those under development in the cancer research community would be used, combining a smart detector of cell chemistry that delivers a not-so-smart kill mechanism, but only to specific cells. At present immunotherapies are the best of these, but there are also selective viral therapies, and others involving nanoparticles. As it turned out, however, all of the more advanced techniques for destroying senescent cells are not targeted at all, and focus on inducing apoptosis, a path to destruction that these cells are already primed to take in comparison to a normal cell. A gentle nudge to the right cellular pathways, such as by increasing or reducing the levels of proteins relevant to apoptosis, will be ignored by near all cells other than those in a senescent state. There, however, it can be enough to tip them over the edge in large numbers. So a senolytic therapy can be delivered generally without targeting. Interestingly, inducing apoptosis is a long-standing line of work in the cancer research community, so there are already stables of drug candidates to explore for use in destruction of senescent cells. If recent deals are any indication, we'll probably see a lot of cross-pollination between these fields in the next few years. Aside from that, a lot of the recent work on senolytic drugs has focused on bcl-2 inhibitors capable of reducing levels of bcl-2, bcl-xl, and bcl-w, all of which act in various ways to suppress apoptosis. This latest published research is along these lines:

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

While the mechanisms driving senescence are well studied, understanding of the mechanisms endowing these cells with increased survival capacity is limited. The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This family includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1 and A1, and is intensively studied as a target for pharmacological intervention in cancer. We set out to evaluate the individual contributions of each of these BCL-2 family members and their combinations to the viability of senescent cells. We found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis, and that their combined inhibition leads to senescent cell death. We show that a small-molecule inhibitor targeting the BCL-2, BCL-W and BCL-XL proteins (ABT-737) causes preferential apoptosis of senescent cells, both in vitro and in vivo, and eliminates these cells from tissues, opening the door for targeted elimination of senescent cells.

In light of the consistent upregulation of BCL-W, BCL-XL and BCl-2 observed in all tested types of senescent cells, we examined the effects of their inhibition on cell viability using ABT-737, a potent small-molecule inhibitor of BCL-2, BCL-XL and BCL-W24. Human senescent cells of all three types were significantly more sensitive than control cells to treatment with ABT-737, showing up to 65% death at the highest concentration tested. The same effect was observed following ABT-737 treatment of senescent and control mouse embryonic fibroblasts (MEFs). These findings indicate that BCL-W, BCL-XL and BCL-2 confer resistance of senescent cells to apoptosis, and their inhibition by ABT-737 triggers cell death specifically in these cells.

Our experiments above showed that ABT-737 treatment causes selective elimination of senescent cells in tissue culture, including of cells that were induced to senesce by direct induction of DNA damage. We therefore set out to test the effectiveness of ABT-737 treatment in elimination of DNA-damage-induced senescent cells in vivo. To this end, we induced lung damage and senescence in mice by ionizing radiation, which causes long-lasting accumulation of senescent cells, readily identified by persistent DNA damage, in the lungs. Seven days after irradiation the mice were treated with ABT-737 for 2 days, and 1 day later the lungs were excised and analysed for the expression of senescence markers. SA-β-Gal staining showed a significant decrease in the amount of senescent cells following ABT-737 treatment. This reduction was accompanied by a significant decrease in the numbers of γH2AX-positive lung cells and a decrease in the expression of the senescence markers p53 and p21. The molecular targets of ABT-737, BCL-XL and BCL-W, were expressed in the irradiated lungs and their levels were reduced as a result of the treatment. The reduction in the expression of senescence markers and ABT-737 target proteins was accompanied by increased caspase-3 cleavage, suggesting an increase in apoptosis in the lung following the treatment. These findings establish that ABT-737 treatment leads to the elimination of senescent cells in vivo.

We next tested whether BCL protein family inhibition by ABT-737 could eliminate senescent cells induced by direct activation of p53 in the skin. To this end, we used transgenic mice in which the human p14ARF gene is inducibly expressed in the basal layer of the skin epidermis. Induction of p14ARF in these mice activates p53 and generates senescent epidermal cells that are retained in the tissue for weeks. To generate senescent cells, we activated expression of p14ARF in 3-week-old mice for a period of 4 weeks, and then treated the mice with ABT-737 for 4 consecutive days. The number of senescent cells in the epidermis, determined by SA-β-Gal staining, was dramatically reduced in the ABT-737-treated mice relative to control mice. A similar degree of elimination was observed after ABT-737 treatment of these mice for 2 days. Concomitantly, the percentage of epidermal cells in which the transgenic p14ARF protein could be detected was reduced, indicating preferred elimination of transgene-expressing cells. Increased levels of apoptosis were detected in the epidermis after 2 days of ABT-737 treatment, consistent with increased apoptosis as the mechanism of senescent cell elimination. These findings indicate that the survival signal provided by BCL-family proteins is an essential component of the ability of senescent cells to be retained in the tissue, and in its absence they rapidly die.

The ability to pharmacologically eliminate senescent cells in vivo opens the door to study the roles of senescent cells in a wide range of physiological settings in which they are detected, and to dissect their beneficial and detrimental functions. Importantly, this is an early step towards potential clinical application of senolytic drugs, in such settings as aging-associated diseases. The chemotherapeutic elimination of senescent cells from premalignant lesions and tumours may also prove beneficial, in particular settings in which a pro-tumorigenic function of senescent cells in the tumour or stroma will be proven. Overall, our findings reveal a central molecular mechanism maintaining the viability and retention of senescent cells in tissues, and suggest that the elimination of senescent cells by inhibition of this mechanism represents a promising strategy for targeting senescent cells during tumourigenesis and age-related diseases.


Below find linked an open access paper that looks at what has to be done to reach the goal of engineered patient-matched organs, built as needed for transplantation, and the resulting end to shortages and waiting lists. It is interesting for putting some figures on the table for time and cost for the various lines of development required. From my perspective, over the longer term of the next twenty to fifty years, the interesting race in tissue engineering and regenerative medicine is between as-needed production of patient-matched tissues and organs for transplant on the one hand and in-situ restoration of all damage in existing tissues and organs on the other. If organs can be comprehensively repaired in place through regenerative medicine, a process that would have to incorporate the SENS portfolio of damage repair therapies for the old, and thus be much more than just an evolution of the stem cell approaches in their infancy today, then there would be little need for transplantation. At present the production of tissues for transplant is much more advanced, however, on the verge of producing useful, functioning sections of internal organs for medicine rather than research.

Thus, over the next couple of decades the immediate race is between the varied established approaches to engineering organs to order, between the range of possible ways to improve transplantation procedures, and between the research groups specializing in different organs or methodologies. These methodologies include decellularization of existing donor organs, xenotransplantation of transgenic pig organs, the bioprinting of tissue scaffolds and cells, and force-growing tissues from stem cells, with the latter still having a long way to go yet. Researchers have demonstrated tiny sections of functional tissue for the kidney, liver, intestines, thymus, and various other organs, but at present these are intended to speed up research. They are only a stepping stone. Scaling up beyond a sliver of tissue is a real challenge, as it involves building complex vascular networks to supply the cells, something that has been a roadblock for more than a decade now, and this despite a great deal of funding, ingenuity, and effort. This is why decellularization and xenotransplantation (or both together) have gathered support and funding: they represent a shorter path to expanding the supply of viable organs.

There are other challenges to the near future of organ engineering beyond those involved in building blood vessel networks of tiny capillaries. All will require time and effort to overcome, and while the scientific community devoted to this work has better funding and support than those involved in aging or rejuvenation research, there is never enough funding or support as would be justified given the end results. No society in history has devoted as much to research as would make sense from a purely logical point of view, sad to say. It is human nature to be consumed by what is, and not with what might be. Progress is an afterthought, which is why even in fields with a sizable output of papers and trials, it is still the case that we need the advocacy of groups like the Methuselah Foundation and the New Organ prize series. Research prizes and contests such as the NASA Vascular Tissue Challenge spur progress, and faster progress towards engineered organs is a good thing indeed.

Bioengineering Priorities on a Path to Ending Organ Shortage

There are four main pathways that we will consider at a high level on a path to end organ shortage through bioengineering: (1) bioprinting organs and tissues, (2) recellularization strategies, (3) cellular repair or regeneration, and (4) xenotransplantation.


3D printing, or layer-by-layer building of organs and tissues, is a process in which cells and intercellular materials are laid out (also referred to as 3D bioprinting, biofabrication, or additive manufacturing) to create a functioning tissue or organ. This living construct would then be implanted into the patient to replace lost organ functionality.

Recellularization Strategies

Through the use of existing tissue scaffolds from other organs or biologic material, new functionality can be provided to patients. These scaffolds must first be cleared of all endogenous cells, and then repopulated with new cells to form a functional bioengineered organ, at which time the newly formed organ would be implanted into the patient. Cells can also be seeded onto/within biodegradable scaffolds that slowly breakdown after implant, leaving only the desired cells and the extracellular matrix they have deposited. One example of promising work in this area is tissue-engineered autologous urethras for patients.

Cellular Repair or Regeneration

In vivo repair/regeneration of damaged organs can be accomplished by delivering small molecules, growth factors, or genetically modified cells into existing organs in a patient. It is expected that the new cells integrating into existing tissues may increase tissue functionality through a paracrine effect, as well as by directly supplementing functional cells. Additionally, growth factors or genome-editing techniques could boost organ functionality or stimulate regeneration. Genome-editing techniques, such as the clustered, regularly interspaced, short palindromic repeat (CRISPR) technology, are showing promise in this area. It is expected that advances in CRISPR and other genetic modification systems could repair tissues that harbor genetic damage as a result of cancer, disease, or trauma, and thereby remove the need for replacement tissues in some patients.


The use of genome-editing of animals to alter immune recognition and prevent organ rejection is another promising area that could help reduce the increasing shortage of donor organs. In principle, suitably modified animal organs could then be transplanted into human patients (xenotransplantation). Much uncertainty remains regarding the appropriate functional and genetic modifications and the necessary safety precautions that would be required for successful xenotransplantation, but some encouraging progress is being made.

Technical Feasibility and Cost to Arrive at Successful Solutions to Bioengineering Challenges and Limitations

We reached out to 35 leaders in the field to delve into each of these challenges and limitations to provide perspectives on the technical feasibility of addressing each of these bioengineering challenges, as well as the estimated cost to arrive at successful solutions for the proposed bioengineering challenges. The majority of those polled (67%) indicated that we have, for the most part, identified the major bioengineering challenges. These cover a wide range of areas, including manufacturing, storage and distribution challenges, regulatory and standards challenges, and technological challenges.

Mapping: 5-10 years, costing 1M-50M

It is important to improve our understanding of the detailed structures and organization of cells within each organ to accurately bioengineer tissues to replace lost functionality. Maps of cell placement, phenotype, function, organization, and interaction have not been created in sufficient detail to reliably provide a blue print to repair or replace the functions of existing organs. The generation of a comprehensive "cellular atlas" for each organ would provide great benefit to reconstruction and repair of organ functionality. This cellular atlas would consist of both genetic and development mapping. In many solution pathways, bioengineered organs will likely not be perfect mimics of native organs, but nonetheless will deliver the functions needed. For example, pancreatic islet transplants delivered into the liver can function, but do not replicate the microenvironmental pancreas map.

Vascularization: 5-15 years, costing 50M-100M

Engineering thick tissues in vivo or ex vivo requires the ability to create an internal vascular system that provides the required nutrients to all cells. This has not yet been achieved for tissues thicker than a few millimeters. In order to engineer thick-tissue organs such as the heart, liver, lung, or kidney, this challenge must be overcome. Some progress has been made toward this goal. For example, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells has been shown to improve vascularization in a bioengineered tissue graft model. Developing strategies such as this to improve vascularization in bioengineered tissues and organs, through the addition of cells, small molecules, biomaterials, or other methods, will aid regenerative mechanisms as well as ensure sufficient diffusion of nutrients and oxygen and removal of waste.

Integration: 5-15 years, costing 100M-1B

The nervous and lymphatic systems are not intentionally reestablished at the time of organ transplant, so it remains unclear if bioengineered tissues and organs will behave in the same manner as their native counterparts, or if they will require additional connections to successfully integrate with the patient's body. A need for innervation and lymphatic drainage may be a complex challenge that varies from one organ to the next. Solutions may also vary with the pathways being pursued. Connecting thick tissues to an existing host's vasculature will require different techniques than integrating new vascularized tissues, or other thin-walled structures. Interesting work has shown nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation. Expanding work such as this to larger tissues, and eventually to bioengineered organs, will be critical to ensure proper organ function.

Immunosuppression: 5-10 years, costing 1M-50M

Immunosuppression has been critical for allowing for graft survival and limiting rejection after organ transplantation. However, the long-term use of immunosuppression carries with it several side-effects, such as progressive renal impairment. When cells or tissues are implanted into new patients, immunosuppression requirements can greatly reduce the quality of life, damage the transplanted organ if left unchecked, and increase the risk of infection, cancer, cardiovascular disease, diabetes mellitus, and others. Immunosuppressive drugs are also expensive. Eliminating the need for immunosuppression would be ideal. This may be addressed by using autologous cell sources, the genetic modification of cells and tissues, and possibly by methods we have not yet conceived to induce tolerance in organ transplantation.

Cell manufacturing and sourcing: 5-10 years, costing 50M-100M

There is great need to create more reliable sources of different types of cells that are required to produce each desired organ function. We do not yet have enough reliable, replicable sources of key cell types that can be provided at economical costs and scale. The purity and quality of existing cell sources must also be improved to better prepare bioengineered tissues and organs. Autologous cell sourcing techniques are preferred to banking of allogeneic sources, as the use of autologous cells would mitigate rejection and minimize the need for immunosuppression requirements; however, allogeneic sources are far more cost-effective.

Envisioned Impact Eliminating Organ Shortage Would Have on Disease and Global Economies

An extensive report on improving organ donation and transplantation was prepared by the RAND Corporation in 2008. This report is comprehensive and interested readers are encouraged to review. The authors provided projections on organ donation and transplantation rates, quality-adjusted life years and life years saved, health risks to patients, living organ donation, cross-border exchange, and health inequalities. Their most favorable scenario projected health benefits including transplanting up to 21,000 more organs annually in the EU, which would save 230,000 life years or gain 219,000 quality-adjusted life years (QALYs). For social impacts, it was predicted that increasing organ transplantation will have a positive effect on quality of life for organ recipients, and will lead to increased participation in both social and working life activities. RAND Europe projects the economic benefits of implementing policies to improve organ donation and transplantation of up to 1.2 billion in potential savings in treatment costs, and productivity gains of up to 5 billion. These calculations are based solely on increasing transplants by 21,000 more organs annually. Imagine the projected savings globally for completely eliminating organ shortage!


In the open access paper linked below, researchers demonstrate modest life extension in the short-lived killifish and zebrafish species by inhibiting a specific portion of the protein machinery inside mitochondria, the power plants of the cell responsible for - among many other things - producing a supply of the chemical energy store molecule adenosine triphosphate (ATP). Mitochondria swarm in animal cells by the hundred. They are the evolved remnants of symbiotic bacteria, contain their own mitochondrial DNA, separate from the chromosomal DNA in the cell nucleus, and still replicate like bacteria even though they are tightly integrated into the cellular processes of monitoring and damage control. The cell culls the herd on a continual basis, destroying mitochondria that show signs of damage.

Mitochondria are known to be important in aging, but there are a number of different mechanisms involved. For one, there is a robust association between the details of mitochondrial biochemistry and longevity across species. Species with more resilient mitochondria, made up of a mix of lipids that is on average more resistant to oxidative damage, tend to be longer lived. Secondly, if mitochondria become dysfunctional or limited in number due to any sort of damage or change in environment - such as the sweeping changes of aging - then tissues with high energy requirements begin to suffer. The brain is particularly vulnerable from this perspective, and loss of mitochondrial function over time is associated with the progression of neurodegenerative conditions. Thirdly, mitochondrial signaling is involved in all sorts of processes known to be associated with aging and longevity, such as programmed cell death and triggering of cellular recycling and maintenance mechanisms. Many of the long-lived mutant lineages created over the past two decades in the lab are characterized by altered mitochondrial function and greater cellular repair activity. Lastly, and probably most importantly, rare forms of mitochondrial damage, such as large deletions in mitochondrial DNA, can evade quality control mechanisms, causing cells to be taken over by mutant mitochondria and fall into a harmful state. These cells grow in number with age, and export large quantities of reactive molecules out into tissues, contributing to many forms of age-related damage. For example, this increases the presence of the oxidized lipids that are the seed for the development of atherosclerosis in blood vessel walls.

The SENS rejuvenation research approach to mitochondrial damage is genetic engineering to create a backup copy of mitochondrial DNA in the cell nucleus. Thus there is always a supply of the necessary proteins, and mitochondria can't fall into a state in which they are malfunctioning due to DNA damage. Nuclear DNA is much more robustly protected and repaired than mitochondrial DNA. The challenge lies in the changes and additions needed to route the generated proteins from the nucleus back to the mitochondria. So far this has been achieved for only a few of the necessary genes, and it is a time-consuming process. Gensight is trialing this technology for a gene involved in an inherited mitochondrial disorder, for example, but everything they come up with as a technology platform is applicable to the end goal of carrying out this backup gene therapy for all mitochondrial genes, so as to remove this contribution to aging.

Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan

Here, we have used the short-lived killifish N. furzeri to perform a longitudinal study of gene expression during adult life. N. furzeri is the shortest-lived vertebrate that can be cultured in captivity and replicates many of the typical hallmarks of aging. The recent sequencing of its genome, and the establishment of genome-editing techniques makes it a convenient model species for experimental investigations on aging in vertebrates. Here, we report the observation that individual N. furzeri of different lifespans differ in their transcript levels at an early adult age. Further, we observed that genome-wide the rate of age-dependent gene modulation was lowest in the longest-lived individuals, suggesting that they are characterized globally by a slower aging rate.

Intuitively, differences in gene expression between individuals that differ in their aging rate should become larger as age progresses. However, we do not observe this consistently as differences between the longevity groups were larger at 10 weeks than at 20 weeks, and numbers of differentially expressed genes between adjacent age steps showed a U-shape. Our observations in N. furzeri are rather consistent with the results of a large-scale study of human aging in the prefrontal cortex: rates of age-dependent changes in gene expression are high during childhood, decline until age 20 years, rise again after 40 years, and, by the age of 60, exceed those observed during teenage years. The main result of this paper is that conditions favoring longevity are laid out during early adult life when inter-individual differences in gene expression are larger, and this result is consistent with observations in C. elegans where knock down of complex I genes or mitochondrial ribosomal proteins during development is necessary and sufficient for life extension.

Reduced mitochondrial mass and function is among the most conserved hallmarks of aging and is specifically observed also in N. furzeri at the levels of gene expression, mitochondrial mass, and mitochondrial functional parameters. Mitochondrial biogenesis is intimately connected to conserved longevity pathways such as the mTOR- and IGF1-pathways. Improved mitochondrial function is currently considered as a crucial component for the health-promoting action of physical exercise and calorie restriction. However, knock down of complex I genes expression induces life-extension in worms and flies. This contradiction between physiological age-dependent regulation and effects observed after genetic manipulations is also observed for another major longevity pathway: the IGF-I pathway. Genetic dampening of IGF-I signaling is life-extending in several models, yet growth hormone and IGF-I concentrations in blood decline during aging. Also, expression of mitochondrial ribosomal proteins declines during aging, but knock down of these proteins induces life-extension.

Complex I of the respiratory chain can be potently inhibited by small molecules, such as rotenone (ROT). The effects of ROT may also be explained by the mitohormesis hypothesis postulating that life-extending interventions act via a transient burst of free radical oxygen species that induce adaptive stress responses. In C. elegans, life-extending effects of calorie restriction or RNAi of the insulin signaling pathway are blocked by antioxidants, and partial inhibition of complex I by ROT prolongs lifespan, generates a burst of ROS, and antioxidants block the life-extending effects of ROT. Increasing the dosage of ROT, however, is life-shortening in N. furzeri, as it is expected by a hormetic effect. Life-extending effects of metformin on mice may also be mediated by mitohormesis, since this drug can inhibit complex I, and effects of metformin in C. elegans were directly linked to mitohormesis via induction of peroxiredoxin.

We observed that treatment with a dose of ROT three orders of magnitude below the median lethal concentration can revert the transcriptional profile of brain, liver, and skin to patterns characteristic of younger animals. This effect was seen not only in N. furzeri, but was replicated in the zebrafish D. rerio, showing that ROT effects are not linked to the peculiar physiology of this short-lived species. In D. rerio, effects of ROT were dependent of the length of treatment: treatment for 3 weeks had a smaller effect than a treatment of 8 weeks. The median lifespan of D. rerio is in the order of 3 years, therefore 8 weeks represent ∼5% of median lifespan indicating that a relatively short treatment can cause rejuvenation of the transcriptome. In summary, our data suggest complex I as a new potential target for prevention of age-related dysfunctions.


There is a portion of the life science community interested in the longevity of plants, though it is fairly disconnected from research into medicine and aging for the animal half of the planet. We can debate whether or not there is anything useful for medical research to be learned from comparing plant species and gaining a better understanding as to why some are much longer-lived than others. After all, researchers already reach for very difference species when beginning investigations of cellular biology relevant to medicine. In the animal-focused aging research familiar to this audience, a great deal of experimentation and exploration is carried out in studies of yeast, a fungus rather than an animal, and yet possessing so many similarities to mammals in its cellular processes that the data can be very useful. Yeast is a long evolutionary distance from humanity, but it is arguably a bigger leap from yeast to plants than it is from humans to yeast. Plants have chloroplasts, and that's just the start of a long list of differences. Early stage research into cellular biochemistry is always a trade-off: much more can be done for a given amount of funding in yeast, flies, and worms, but many of those results will fail to also prove relevant in mice, let alone in humans. So far the collective wisdom of the life science research community has declared that yeast passes the cost-benefit equation, while anything with a chloroplast does not.

There are of course, always heretics willing to argue the point, but that is the way science progresses. In the research noted here, a stem cell angle is pursued, and this is one of the areas where I could perhaps be persuaded there might be something useful to be learned from plant life science. If investigations of hydra and their continuous regeneration - and how that relates to mammalian stem cell biology - are worthwhile, then so might be research into the continuous regeneration of some plant species. Still, this is about as close to fundamental research as one can get, which means it is a part of the long-term gathering of information, with no presently plausible application to medical science, and we can only speculate as to where any part of it might prove useful in the decades ahead.

Mechanism Behind Extreme Longevity in Some Plants

Compared to humans' century-long life span, some plants - evergreens in particular - have the capacity to live for an exceptionally long time, even millennia. Researchers zeroed in the formation of axillary meristems - stem cells that give rise to branches - in Arabidopsis thaliana and tomato, finding few cell divisions between the apical meristem located at the very top of a plant and the axillary meristems. With such little proliferation comes less opportunity to accumulate potentially deleterious genetic mutations in somatic cells that could kill the organism, the authors reasoned. "Meristem aging is not a problem for perennial plants, in other words. The meristems are the growing units. If they don't senesce, then the plant will keep the capacity to grow and reproduce forever, at least potentially." Instead, structural defects or pathogens most often kill plants.

In tomato, "it turns out all the cells around are making lots of cell divisions to make leaves and stems, but few cells are destined to become the axillary meristem. Those really don't divide." If the same is true in other species, the results suggest that most plants have something akin to the germline in animals. "That is, plants seem to set aside some cells in such a way as to minimise the number of mutations they accumulate."

One project underway in Switzerland could lend empirical data to test the group's hypothesis. The Napoleome project is an effort to sequence the full genome of a 238-year-old oak tree. The team has actually sequenced two genomes, taken from different parts of the tree, to see how many mutations are present and whether these distant sites share any mutations. "This meristem hypothesis is what we're testing basically with our project. No one has an idea of how many somatic mutations are in an old tree that has lived outside for more than 200 years." Whether this mechanism to limit somatic mutations was selected for evolutionarily to increase longevity or protect the germline "remains an open question, and one that would be very tricky to answer."

Patterns of Stem Cell Divisions Contribute to Plant Longevity

The lifespan of plants ranges from a few weeks in annuals to thousands of years in trees. It is hard to explain such extreme longevity considering that DNA replication errors inevitably cause mutations. Without purging through meiotic recombination, the accumulation of somatic mutations will eventually result in mutational meltdown, a phenomenon known as Muller's ratchet. Nevertheless, the lifespan of trees is limited more often by incidental disease or structural damage than by genetic aging. The key determinants of tree architecture are the axillary meristems, which form in the axils of leaves and grow out to form branches. The number of branches is low in annual plants, but in perennial plants iterative branching can result in thousands of terminal branches.

Here, we use stem cell ablation and quantitative cell-lineage analysis to show that axillary meristems are set aside early, analogous to the metazoan germline. While neighboring cells divide vigorously, axillary meristem precursors maintain a quiescent state, with only 7-9 cell divisions occurring between the apical and axillary meristem. During iterative branching, the number of branches increases exponentially, while the number of cell divisions increases linearly. Moreover, computational modeling shows that stem cell arrangement and positioning of axillary meristems distribute somatic mutations around the main shoot, preventing their fixation and maximizing genetic heterogeneity. These features slow down Muller's ratchet and thereby extend lifespan.


The small, forty-year-old cryonics industry offers indefinite low-temperature storage of at least your brain following death. In a well-organized cryopreservation, the medical team is right there when you die, and cooldown and infusion with cryoprotectant solution can begin immediately. The result is vitrification of tissue, especially brain tissue, to preserve the fine structure that stores the data of the mind. Then you wait, suspended, in liquid nitrogen in a dewar vessel, heading for an uncertain future in which the possibility of restoration exists. That possibility is what you are paying for, and it is the single most important difference between cryopreservation and all the other choices you have at the end of life. Those other choices offer only the certainty of oblivion, but for so long as the data of the mind exists, so long as there is continuity of preservation, then sufficiently advanced molecular nanotechnology and biotechnology will one day be capable of restoring you to life. In a world in which a small but growing number of people are striving to build rejuvenation therapies to defeat aging, and the timeline for that defeat is very uncertain, cryonics is the only available backup plan.

Personally, I don't see much uncertainty in the golden future of transcendent technology that lies ahead. It will happen. The uncertainties all lie in the timing of that technological progress, how long continuity of preservation and preservation organizations can be sustained, and most of all in arranging the slings, arrows, and final moments such that the medical team is in fact right there and waiting when you die. That last one is the hardest part, and will remain so until the laws on euthanasia become more civilized in more parts of the world. If we could be allowed to choose our time, then all cryopreservations could be well-run, minimizing tissue damage and cell loss, and be largely free from large and unexpected costs. Sadly that's all too rarely the case. Even people in very late life are surprised by their own final decline, and all too few make the serious effort to ensure that the unexpected is caught, or at least that it is going to happen in a location at which the cryopreservation organization can muster a very quick response. That it is illegal for people to help you in this situation through euthanasia is just the final indignity, a reminder that civilized and compassionate behavior on the part of those in positions of power remains a still-thin veneer.

What I wanted to talk about here is related to all of this, but not really discussed all that much in the cryonics community. I think it might be one of those things that is so taken as read in the core community of supporters that people don't put much thought into it. Cryonics organizations are non-profits with a membership structure: you pay a monthly or annual fee, and have a variety of options when it comes to ensuring funding for your ultimate cryopreservation, an event hopefully still decades away at the very least. Cryopreservation is in effect a form of surgery, plus other items, involving a group of medical and technical folk with specialized tools carrying out a procedure, and so the costs are similar to those of a surgical procedure - which works out to anywhere from 30,000 to 200,000 depending on the organization and the details of the arrangement. Most people opt to pay using life insurance, since a contract for even 200,000 is pretty cheap on a monthly basis if you are healthy and young, and a life insurance policy can be set up so that the mechanisms of payment will go into effect robustly on your death with no need for micromanagement at a time when you are unlikely to be capable of that effort.

However, this isn't a case of a transfer of funds today, where you see you need to pay 200,000, so you set up a policy for 200,000 and you are done. No. The cost of the cryopreservation agreement today is that 200,000, but that amount will rise with inflation. Thus you take out a life insurance policy that also grows with time. There are many varieties of growth policies, all using different models to try to keep up with inflation while still making a profit for the insurance company. Sometimes they will work, sometimes not, but the people involved in setting up these instruments are all pretty motivated by competition to try to adjust to keep up. Still, we are talking about trying to match the future inflated amounts of two very different things half a lifetime or more from now. If you look at the rule of 72, you'll see that even for plausible levels of inflation on the part of a government that more or less achieves the level of debasement of currency that it aims at, costs will double several times between youth and old age: it is not implausible to expect the 200,000 cryopreservation you signed up for to cost 800,000 four decades from now. If the US meanders into another period like the 1970s, the situation could be much worse than that. If rejuvenation biotechnology goes the way I hope it does, then the horizon and the financial uncertainty expands further. Not that you can't adjust along the way, but that is always going to be more expensive than just being right at the start. Given this, the smart thing to do is to make the life insurance policy larger than it has to be at the outset, especially since that choice costs little. Overfunding the policy shifts the odds greatly in your favor when it comes to the life insurance payout being larger than the cost of cryopreservation on the day that bill is due.

This matter of uncertainty in inflation and financial instruments is not the only reason to have a larger life insurance policy than the minimum needed. Consider that there are any number of things that can go wrong at the end of life, greatly increasing the costs incurred by the cryonics organization. Yes, once you and the cryonics technicians are in the same room, everything is practiced and under control, but before that point there are many ways to run off the rails. You could be in an inconvenient location, local government officials or family members could interfere and require legal efforts to deal with, flights might have to be chartered at short notice, and so on and so forth. Any one of these could easily balloon into a few tens of thousands of additional costs today. If you look back through the history of cryopreservations in which the details have been made public, such as those published by Alcor, there are many cautionary tales, and more than a few cases in which everyone involved did the right thing and costly problems still occurred. If the hurdles put in place by chance or opponents are too costly for the cryonics organization to overcome, given the funding you have put in place, or that others can supplement at the time, then you won't be preserved. Cryonics providers will make absolutely the best effort possible, and again, if you look at the history there are many cases in which companies and volunteers have gone above and beyond to make a cryopreservation happen, but they won't damage or risk the sustainability of the entire organization for one person. Lines have to be drawn.

So, again, assume the worst, and when sorting out life insurance apply for more than the minimum needed to fund your cryopreservation. Twice the minimum is not unreasonable: nothing in life is certain, and it is better to be safe than sorry when being safe costs little. It is all about swinging the odds more in your favor. If the extra funds turn out not to be needed, then they can be directed to a charity, or to sustaining the cryonics organization, or its research efforts, or another worthy goal. Some people even set up forms of perpetual trust, another experiment with an uncertain chance of success, but which may lead to there being some personal funds to continue with in the case of restoration. Certainly from an immediate and practical point of view, all of the cryonics organizations advise in their materials that you overfund your policy, but they tend to say as much and move on. There's less in the way of accessible discussion out there that goes through the reasons as to why this is the case. Hopefully this small contribution helps.



The lysosome is a type of cellular component that serves as a recycling unit, breaking down unwanted proteins and structures into their raw materials. As such they play an important role in cellular housekeeping, the removal of damaged structures, machinery, and waste that will, if left unchecked, harm cells and cellular processes. Unfortunately not all byproducts of metabolism can be broken down, either efficiently or at all, and in long-lived cell populations lysosomes become bloated and dysfunctional, filled with a mix of hardy waste products called lipofusin, and much less able to perform their recycling activities. This contributes to the progression of aging, leading to a sort of runaway garbage catastrophe.

Researchers have demonstrated that improving lysosomal function, even without addressing the issue of liposfusin, can greatly improve measures of organ function in older animals. The SENS rejuvenation research approach to this aspect of aging is to find ways to break down the important constituents of lipofuscin by mining the bacterial world for suitable enzymes capable of digesting it. We know they exist because lipofuscin doesn't build up in the soil of graveyards. At present this work has produced some candidates, and is slowly heading in the direction of initial commercial development - though as for near all lines of research relating to repair of the causes of aging, there is all too little interest and funding.

Lysosomes are found in all animal cell types (except erythrocytes) and represent the cell's main catabolic organelles. The variety of substrates degraded in the lysosomes is wide, ranging from intracellular macromolecules and organelles to surface receptors and pathogens, among others. However, lysosomes are not mere sites for disposal and processing of cellular waste but also act as pivotal regulators of cell homeostasis at different levels. For instance, they are involved in the regulation of cellular responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation, among many others. Thus, lysosomes play a determining role in processes that control cellular and organismal life and death. Concurring with this pleiotropic importance, lysosomal dysfunction is associated to a plethora of disorders. Notably, lysosomal defects disturb the balance between damaged proteins and their proteolytic clearance, ultimately resulting in the accumulation of highly cross-linked aggregates. Accumulation of aggregates in post-mitotic cells appears to be particularly dramatic, since the material cannot be diluted via cell division. Many resulting aggregates of oxidized proteins may further react with cellular components like lipids and metals in different compositions, forming a fluorescent material termed lipofuscin. Indeed, the aging process itself may be fueled by a decrease in lysosomal function.

Mounting evidence suggests that a cell's lifespan is partly determined by lysosomal function. This implies that processes in which lysosomes are generally involved, but which have not been clearly associated to aging yet, might also directly or indirectly modulate longevity. Lysosomal exocytosis, for example, in which lysosomes dock to the cell surface, fuse with the plasma membrane and release their content into the extracellular space, has an important role in membrane repair and may contribute to intracellular regeneration upon cellular senescence. At the same time, lysosomal exocytosis is involved in secretion processes that could interact with aging-related intercellular signals at the tissue and organismal level and/or help alleviate intracellular stress conditions, possibly in cooperation with selective secretion through exosomes. Interestingly, lysosomal exocytosis is modulated by Ca2+ and TFEB, both of which have regulatory functions during aging.

On the other hand, molecular processes known to impact aging may at least partly do so because they affect lysosomal function. Such processes may engage single components of the cellular network that are involved in lifespan control, including mitochondria, the nucleus, or peroxisomes. Intriguingly, lysosomes not only communicate with other organelles in the frame of their autophagic removal. For example, the peroxisome-lysosome interaction does not seem to be restricted to pexophagy. The membranes of both organelles can come in close apposition (without fusion), creating lysosomal-peroxisome membrane contacts (LPMC), which are essential for the cellular trafficking of cholesterol. Interestingly, cholesterol oxide derivatives (oxysterols) are involved in different aging-relevant processes like redox equilibrium and inflammation. In addition, they have been associated to major age-related pathologies like neurodegenerative and cardiovascular diseases. Thus, organelles associated with the generation, transformation and transport of such molecules may strongly influence their impact on aging. The occurrence of membrane tethering sites (microdomains) like LPMCs allows an efficient interplay between organelles. Thus, the establishment of microdomains between lysosomes and other organelles may allow signal exchanges that contribute to a dynamic and orchestrated control of aging. Though some remain speculative in their causality, these lysosome-aging connections exemplify the multilayered mechanisms through which lysosomal function may crucially contribute to aging control. Recognizing this potential opens doors not only to further understand the process of aging but also to improve the ravages of time via lysosomal avenues.


Researchers here make an attempt to extract some insight into causation from longitudinal data on retirement age and subsequent mortality rates. If continuing to work on balance involves undertaking more physical activity than would otherwise be the case, it isn't unreasonable to think that this might be a possible mechanism of causation, given the existing evidence for even low levels of activity such as that involved in cleaning and gardening to make a measurable difference to health and life expectancy in later life. Still, the data in this study isn't particularly compelling in and of itself; it has to be considered in the context of other research.

Researchers examined data collected from 1992 through 2010 through the Health and Retirement Study, a long-term study of U.S. adults. Of the more than 12,000 initial participants in the study, the focus narrowed to 2,956 people who began the study in 1992 and had retired by the end of the study period in 2010. "Most research in this area has focused on the economic impacts of delaying retirement. I thought it might be good to look at the health impacts. People in the U.S. have more flexibility about when they retire compared to other countries, so it made sense to look at data from the U.S."

Poor health is one reason people retire early and also can lead to earlier death, so researchers wanted to find a way to mitigate a potential bias in that regard. To do so, they divided the group into unhealthy retirees, or those who indicated that health was a factor in their decision to retire - and healthy retirees, who indicated health was not a factor. About two-thirds of the group fell into the healthy category, while a third were in the unhealthy category. During the study period, about 12 percent of the healthy and 25.6 percent of the unhealthy retirees died. Healthy retirees who worked a year longer had an 11 percent lower risk of mortality, while unhealthy retirees who worked a year longer had a 9 percent lower mortality risk. Working a year longer had a positive impact on the study participants' mortality rate regardless of their health status.

"The healthy group is generally more advantaged in terms of education, wealth, health behaviors and lifestyle, but taking all of those issues into account, the pattern still remained. The findings seem to indicate that people who remain active and engaged gain a benefit from that. Additional research is needed to better understand the links between work and health, the researchers said. As people get older their physical health and cognitive function are likely to decline, which could affect both their ability to work and their longevity. "This is just the tip of the iceberg. We see the relationship between work and longevity, but we don't know everything about people's lives, health and well-being after retirement that could be influencing their longevity."


Researchers have published an interesting set of results from one of a number of human studies of moderate calorie restriction that have taken place over the past decade. Reduced calorie intake has a beneficial effect on long-term health, producing outcomes in human and animal studies that no presently available medical technology can match, because no presently available medical technology slows progression of the cell and tissue damage that causes aging to the same breadth and degree. That is all the more reason to put more effort into producing therapies capable of treating these causes of aging, but why not take advantage of benefits that are free while waiting for rejuvenation therapies to arrive? There is some speculation as to the degree to which benefits resulting from calorie restriction are due to carrying around less visceral fat, tissue that contributes to chronic inflammation, but research demonstrates that there is a lot more than that going on. Calorie restriction moves almost all measures of metabolic activity, and among many other things spurs greater cellular housekeeping activities, for example.

A 25 percent calorie restriction over two years by adults who were not obese was linked to better health-related quality of life, according to the results of a randomized clinical trial. Researchers tested the effects of calorie restriction on aspects of quality of life that have been speculated to be negatively affected by calorie restriction, including decreased libido, lower stamina, depressed mood and irritability. Their work extends the literature with a study group of nonobese individuals because beneficial effects of calorie restriction on health span (length of time free of disease) increase the possibility that more people will practice calorie restriction.

In this clinical trial conducted at three academic research institutions, 220 men and women with body mass index of 22 to 28 were enrolled and divided almost 2 to 1 into two groups: the larger group was assigned to two years of 25 percent calorie restriction and the other was an ad libitum (their own preference) control group for comparison. The analysis included 218 participants and self-report questionnaires were used to measure mood, quality of life, sleep and sexual function. Data were collected at baseline, a year and two years. Of the 218 participants, the average age was nearly 38 and 70 percent were women. The calorie restriction group lost an average of 16.7 pounds compared with less than a pound in the control group at year two.

According to the authors, the calorie restriction group, compared with the control group, had improved mood, reduced tension and improved general health and sexual drive and relationship at year two, as well as improved sleep at year one. The bigger weight loss by the calorie restriction participants was associated with increased vigor, less mood disturbance, improved general health and better quality of sleep. "Calorie restriction among primarily overweight and obese persons has been found to improve quality of life, sleep and sexual function, and the results of the present study indicate that two years of calorie restriction is unlikely to negatively affect these factors in healthy adults; rather, CR is likely to provide some improvement."


In recent years human studies of exercise and life expectancy have pointed to a correlation between time spent sedentary and mortality rate, and this correlation appears to be independent of the level of regular exercise undertaken. Here researchers look to calcification as a possible mechanism to explain this association. Calcification of blood vessels and heart tissue occurs with age, and contributes to the tissue stiffness that leads to hypertension, followed by detrimental remodeling of the heart and vascular system to try to compensate. At the end of that road lies cardiovascular disease and death. It isn't completely clear as to whether calcification will occur to a significant degree even if other forms of cell and tissue damage known to cause vascular aging can be repaired, in other words whether calcification is an entirely secondary process of aging. Given that uncertainty it is probably worth adding it as a target for future regenerative therapies.

Researchers have found that sedentary behavior is associated with increased amounts of calcium deposits in heart arteries, which in turn is associated with a higher risk of heart attack. The researchers had previously shown that excessive sitting is associated with reduced cardiorespiratory fitness and a higher risk of heart disease. The latest research - part of the Dallas Heart Study - points to a likely mechanism by which sitting leads to heart disease. "This is one of the first studies to show that sitting time is associated with early markers of atherosclerosis buildup in the heart. Each additional hour of daily sedentary time is associated with a 12 percent higher likelihood of coronary artery calcification." The researchers concluded that reducing daily "sitting time" by even 1 to 2 hours per day could have a significant and positive impact on future cardiovascular health, and called for additional studies into novel interventions to reduce sedentary behaviors. For the many individuals with a desk job that requires them to sit for large portions of the day, they suggested taking frequent breaks.

In some individuals, cholesterol builds up inside the walls of the arteries supplying blood to the heart in mounds called cholesterol plaques. Over time, calcium accumulates in these plaques. The amount of coronary artery calcium can be measured through CT scanning and directly correlates with the amount of cholesterol plaque, as well as with heart attack risk. In this study, the researchers asked some 2,000 participants in the Dallas Heart Study to wear a device that measured their activity levels for a week. Participants spent an average of 5.1 hours sitting per day and an average of 29 minutes in moderate to vigorous physical activity each day. "We observed a significant association between increased sedentary time and coronary artery calcium. These associations were independent of exercise, traditional cardiovascular disease risk factors such as diabetes and high blood pressure, and socioeconomic factors. This research suggests that increased subclinical atherosclerosis characterized by calcium deposition is one of the mechanisms through which sedentary behavior increases cardiovascular risk and that this risk is distinct from the protective power of exercise."


Here researchers investigate how immune cells in the brain work to fix tiny breakages of blood vessels. The link between vascular aging and neurodegeneration is most likely largely driven by breakage of blood vessels in the brain. Increased stiffening of vessels and increased blood pressure causes an ever greater frequency of microbleeds, each a tiny unnoticed stroke in essence, destroying a small piece of brain tissue. Over time that destruction adds up. The ideal treatment is to periodically repair the damage that causes stiffness and other deterioration in blood vessels, such as cross-linking, calcification, and mechanisms of atherosclerosis involving oxidized lipids and macrophage behavior, thus preventing breakages. Enhancing repair of the blood vessels after the fact of breakage is probably also useful, though the damage to neural tissue may be done by that point.

As we age, tiny blood vessels in the brain stiffen and sometimes rupture, causing "microbleeds." This damage has been associated with neurodegenerative diseases and cognitive decline, but whether the brain can naturally repair itself beyond growing new blood-vessel tissue has been unknown. A zebrafish study now describes for the first time how white blood cells called macrophages can grab the broken ends of a blood vessel and stick them back together. "We believe that this macrophage behavior is the major cellular mechanism to repair ruptures of blood vessels and avoid microbleeding in the brain."

To simulate a human brain microbleed, researchers shot lasers into the brains of live zebrafish to rupture small blood vessels, creating a clean split in the tissue with two broken ends. Then, the researchers used a specialized microscope to watch what happened next. The repair process started about a half hour after the laser injury. A macrophage showed up at the damaged blood vessel site and extended two "arms" from its body toward the ends of the broken blood vessel, producing a variety of adhesion molecules to attach itself. Then, it pulled the two broken ends together to mediate their repair. The researchers suspect that adhesion molecules produced by the blood-vessel tissue also play a role in reattachment. Once they were adhered, the macrophage left the scene. The whole process took about three hours. "After we confirmed that the macrophage mediates this repair through direct physical adhesion and generation of mechanical traction forces, we were excited. This is a previously unexpected role of macrophages."

A similar repair process also occurred outside the brain. When the researchers ruptured a blood vessel in the zebrafish fin using a laser, a macrophage arrived at the injury site and extended its protrusions to pull the broken blood vessel back together. The researchers did observe a few quirks in the process. When they used a laser strike to destroy the first macrophage that arrived at a laser-wound site in the brain, no other macrophages came to help repair the breakage (but another macrophage arrived to eat the dead one). Rarely, two macrophages would arrive at the injury on their own, each grab a broken end of the blood vessel, and then simply disengage without fixing the damage. Macrophages aren't the brain's only repair mechanism for small broken blood vessels, though they look to be the fastest and most efficient.


The various heat shock proteins play a role in the hormetic response to damage. When damaged, cells dial up their repair activities for a while, and if the damage is mild and brief, the result is a net gain in quality control. Less damage means less dysfunction, and this is why increased cellular maintenance activities are involved in many of the methods demonstrated to modestly slow aging in animal studies. It is possible to dial up maintenance without using damage as a trigger, through suitable changes to levels of proteins, such as genetic engineering to increase the production of heat shock proteins:

Intrinsic cardiac aging is defined as slowly progressive functional declines and structural changes with age, in the absence of major cardiovascular risks such as hypertension, diabetes, hypercholesterolemia, and smoking. However, intrinsic cardiac aging can increase the vulnerability of the heart to both endogenous and exogenous stressors, ultimately increasing cardiovascular mortality and morbidity in elderly individuals. Therefore, interventions to combat cardiac aging not only will improve the healthspan of the elderly, but also can extend their lifespan by delaying cardiovascular disease-related deaths. Studies indicate that the pathogenesis of cardiac aging involves multiple molecular mechanisms, including oxidative stress, impaired autophagy, metabolic changes, dysregulated calcium homeostasis, and activation of neurohormonal signaling. Indeed, the reactive oxygen species (ROS) content significantly increases in the aged heart, while mitochondrial overexpression of catalase (an important antioxidative enzyme) improves the aging-induced decline in cardiac function and prolongs the lifespan of mice. Intracellular ROS in the aged heart are mainly generated from damaged mitochondria. In normal conditions, damaged mitochondria are selectively degraded through autophagy, a process known as mitophagy. Unfortunately, autophagy is progressively impaired over time.

Heat shock protein 27 (HSP27) is an ubiquitously expressed member of the small heat shock protein subfamily. Studies demonstrated the involvement of HSP27 in various biological functions, including the responses to oxidative stress, heat shock, and hypoxic/ischemia injury. Of particular interest to this study, we and others showed that overexpression of HSP27 protects cardiac function against cardiac injuries induced by ischemia/reperfusion, myocardial infarction, inflammation, and doxorubicin. The mechanisms that contribute to cardioprotection by HSP27 involve the antioxidative capacity, suppression of inflammatory responses, improvement of cardiomyocyte survival, and activation of autophagy and mitochondrial activity. It is possible, therefore, that overexpression of HSP27 protects the heart from aging-induced injury.

In this study, we examined the effects of HSP27 on cardiac aging using transgenic (Tg) mice with cardiac-specific expression of HSP27. We observed an improvement in cardiac function and decreases in the levels of cardiac aging markers in old Tg mice compared with age-matched wild-type (WT) controls. This action of HSP27 involves the antioxidative capacity and activation of mitochondrial autophagy (mitophagy). Our results suggest that management of HSP27 expression may serve as an alternative intervention to alleviate cardiac aging.


For more than a decade there has been some interest in the research community in developing treatments based on enhancing the cellular maintenance processes of autophagy. Higher levels of autophagy feature in many of the established animal lineages with modestly extended healthy longevity, created through genetic manipulation. Despite this interest, and a growing number of drug candidates, there has been little progress in moving towards trials or clinical translation, however. This paper describes another new drug candidate:

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies.

Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer's disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.


Research from the past few years has demonstrated that far better correlations between weight and mortality can be obtained by considering the history of individual weight rather than just taking snapshots of populations at a moment in time. In particular, some studies produced results suggesting that being overweight has a lower mortality rate in older age, but this happened as a result of failing to consider weight changes in the studied populations; following work has fairly comprehensively torn down those results. Consider that, for example, a fair number of thinner old people were overweight when younger but suffer from chronic medical conditions that produce both weight loss and much higher mortality. They distort the data, being completely different from people who were always thinner and are as a result healthier in old age. This is why you can't put all people who are thin at a given moment in time into one statistical bucket and expect sensible data on the other side of the calculations: garbage in, garbage out. The publicity materials linked here cover studies that provide more data along these same lines:

People who are lean for life have the lowest mortality, while those with a heavy body shape from childhood up to middle age have the highest mortality, reveal findings of a large study. Researchers tracked the evolution of body shape and associated mortality among two large cohort studies. In total, 80,266 women and 36,622 men enrolled in the Nurses' Health Study and Health Professionals Follow-up Study, recalled their body shape at ages 5, 10, 20, 30, and 40 years. They also provided body mass index at age 50, and were followed from age 60 over a median of 15-16 years for death. They answered detailed questionnaires on lifestyle and medical information every two years, and on diet every four years.

Among the cohort, five distinct body shapes were identified from age 5 to 50: lean-stable, lean-moderate increase, lean-marked increase, medium-stable/increase, and heavy-stable/increase. Results showed that people who remained stably lean throughout life had the lowest mortality, with a 15-year risk of death being 11.8% in women, and 20.3% in men. Those who reported being heavy as children and who remained heavy or gained further weight, especially during middle age, had the highest mortality, with a 15-year risk of death being 19.7% in women and 24.1% in men. The authors conclude: "our findings provide further scientific rationale for recommendations of weight management, especially avoidance of weight gain in middle life, for long-term health benefit."

In a second study, an international team of researchers confirm that increasing levels of body mass index (BMI) are associated with higher risks of premature death. The BMI is an established way of measuring body fat from the weight and height of a person, but the optimal BMI associated with the lowest mortality risk is not known. It's expected that a higher BMI is associated with a reduced life expectancy, but the largest previous study showed that when compared with normal weight, overweight was associated with reduced mortality, and only high levels obesity were associated with increased mortality.

So researchers in the current study sought to clarify this association by carrying out a large meta-analysis of 230 prospective studies with more than 3.74 million deaths among more than 30.3 million participants. They analysed people who never smoked to rule out the effects of smoking, and the lowest mortality was observed in the BMI range 23-24 among this group. Lowest mortality was found in the BMI range 22-23 among healthy never smokers, excluding people with prevalent diseases. And among people who never smoked, and studied over a longer duration of follow up of more than 20 and 25 years, where the influence of prediagnostic weight loss would be less, the lowest mortality was observed in the BMI range 20-22.


This open access paper describes data on epigenetic and protein abundance changes with age in the liver and brain in rats. It is a good introduction to just how much data is yet to be cataloged in detail when looking at all tissue and cell types and how their operations change with aging. The sheer complexity of our biochemistry is why shortcuts that enable us to evade waiting on more data are essential to rapid progress towards rejuvenation treatments. At present, for example, the forms of damage that distinguish old tissue from young tissue are well enumerated and well understood. So the research community can work towards repair therapies without needing to fill in any of the blanks regarding exactly how this damage produces the very complex set of alterations and wide range of age-related diseases seen in old tissues.

Here, we present an integrated comparison of gene expression, translation, protein abundance, and phosphorylation in organs from young and old rats. Our work expands the list of proteins that are affected by chronological age in mammals. Although some of the functional modules discussed above were previously identified as hallmarks of aging, we identified hundreds of molecular events underlying these processes that were previously unknown to be affected by age. We thus provide a rich resource that should stimulate the generation of new, experimentally testable hypotheses, leading to a better understanding of aging on the organism level.

The comparison of two organs with different physiology and regenerative capacity enabled us to distinguish organ-specific effects from more systemic effects of aging. Intuitively, our results suggest that organ-specific effects of age are tightly linked to the organ function. For example, in brain, multiple alterations of key signaling mediators are observed. We speculate that these alterations might be part of a progressive functional deterioration that affect the maintenance of neuronal plasticity in old brains and other phenotypes observed the aging brain. Notably, 45 of the changes that we identified in old rat brains are consistent with a previous transcriptomics study of aging human brains, suggesting that age-related changes in the proteome and transcriptome are to some extent conserved from rat to humans.

The systemic impact of chronological age on proteome homeostasis manifests on many levels. In the liver, the majority of age-dependent changes are driven by alteration of transcript abundance (58% of the affected transcripts versus only 25% in brain), suggesting the occurrence of age-related changes in transcriptional regulation. In contrast, the brain appeared to be affected by age largely at the translational level. Our data suggest that an age-associated remodeling of the translation machinery in the brain may ultimately lead to alterations of the translation efficiency of a subset of transcripts in old animals. Specifically, we identified 15% of the brain transcripts to be affected by a change in translation (versus only 2% in liver).

Despite the correlation between translation output and protein abundances, not all the observed changes of protein abundance could be explained by changes in translation output, particularly in brain. This phenomenon strongly indicates a higher degree of post-translational control in the brain as compared to the liver. Indeed, our proteomic analysis revealed that key regulators of protein homeostasis were altered in aged brain, including several components of the ubiquitin-proteasome and autophagy systems. These findings imply that altered protein homeostasis, which has been shown to affect organism longevity under stress-response conditions, also leads to detectable proteomic alterations that occur between young and old animals. The exact consequences and targets of such alterations are likely complex and remain to be explored in detail.


This very readable paper discusses the possible role for ceramides in the processes of aging relevant to declining fitness and muscle function. This is all some steps removed from the fundamental cell and tissue damage that causes aging, however, and is really a discussion of the details of a small snapshot of later, complicated reactions to that damage. That said, it is very representative of most present research into aging by groups that lean towards producing possible therapies. Interventions are planned for later consequences in aging, without addressing the root causes of observed disruptions and alterations.

Aging is associated with a progressive loss of cardiorespiratory fitness, which in turn leads to an increased risk of morbidity and mortality. Cardiorespiratory fitness is defined as maximal oxygen consumption (VO2 peak) during dynamic exercise and is typically measured during a graded exercise test. Using this operational definition, the decline in fitness starts around the age of thirty and continues at approximately 10% per decade. It accelerates even further toward the end of the lifespan, even in healthy persons. Cardiorespiratory fitness is a critical determinant of physical function in older adults and an accurate indicator of cardiovascular and overall health. Thus, maintaining a good level of fitness is fundamental to delaying mobility difficulty and attaining healthy longevity.

Maximal oxygen consumption is largely explained by cardiovascular adaptations in transporting oxygen to muscle as well as mitochondrial adaptations within muscle, to meet the energy demands of physical activity. Recent evidence suggests that the capacity for vasodilatation in the peripheral vasculature also plays an important role in maximal oxygen uptake. The decline in VO2 peak with aging has been primarily attributed to the reductions in muscle oxygen delivery, due to decreased cardiac output, and to the reductions in skeletal muscle oxidative capacity, mainly due to the mitochondrial dysfunction. However, there is a wide interindividual variability in the rate of decline, which is only partially explained by differences in physical activity. Thus, studies of biological correlates of physical fitness are important because they may provide insight as to why some individuals experience an accelerated decline of aerobic capacity. Further, such correlations may serve as clinically valuable prognostic indicators of cardiovascular health, morbidity, and mortality risk.

Ceramides are a ubiquitous group of lipids that consist of a sphingosine linked to a fatty acid. Ceramides are known for their structural role in plasma membranes and also as important signaling molecules involved in many essential cellular processes including inflammation, immune cell trafficking, vascular and epithelial integrity, apoptosis, autophagy, and stress responses. In the circulation, ceramides are transported primarily in low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). Previous studies suggested that ceramides increase with age and are associated with accelerated aging and age-related chronic conditions, particularly cardiovascular and metabolic diseases. Treatments targeting ceramides may be potentially very effective for preventing or treating these conditions. For example, elevated plasma ceramides cause vascular endothelial dysfunction by promoting endothelial cell growth arrest, oxidative stress, senescence and death, disrupting insulin signaling and increasing inflammation. Perhaps through these same mechanisms, ceramides may contribute to the early stages of atherosclerosis.

Given the evidence linking ceramide to mechanisms fundamental to cardiovascular health in cell culture and animal studies, we examined the relationships between ceramides and indicators of cardiovascular health in older adults. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity. The associations held true for both sexes (with men having a stronger association than women) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long-chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging.


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