The fifth Strategies for Engineered Negligible Senescence (SENS) Conference, SENS5, draws closer. It will be held from 31st August to 4th September at Queens' College in Cambridge - so there's still time to register.

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

The program of presentations links to a range of interesting abstracts describing some of the important work that has taken place in the couple of years since SENS4, such as:

Tissue engineering of the liver using decellularised scaffolds

Here, we describe the fabrication of three-dimensional, naturally derived scaffolds with an intact vascular tree. ... The vascular network was used to reseed the scaffolds with human fetal liver and endothelial cells. These cells engrafted in their putative native locations within the decellularized organ and displayed typical endothelial, hepatic and biliary epithelial markers, thus creating a liver-like tissue in vitro.

MitoSENS: Allotopic expression of mitochondrial genes using a co-translational import strategy

The mitochondrion contains its own genome and encodes 13 proteins that are essential for the respiratory chain to function properly, [but] somatic mutations also accumulate in the mitochondria with normal aging. ... Thus far, we have stably transfected 5 of the 13 mitochondrial genes into the nuclear genome of human cell lines and are characterizing the expression and function of these exogenously expressed genes.

I also note that the group in Florida who are running a trial of granulocyte transplant therapy for cancer - based on the impressive results achieved by Zheng Cui - will also be presenting. On the whole, the program is well worth browsing. If you are interested in this field of science and biotechnology and you are not yet signed up for the conference, you should give some thought to attending.

An open access paper: "One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar [or shared biological pathways], like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. ... Stem cell restoration has already demonstrated therapeutic activities in certain systems. For example, it is known that after a stroke, endogenous stem cells are mobilized from the bone marrow in an attempt to heal the damaged neural tissue. Most interestingly, a recent study demonstrated that stroke patients who exhibit a high level of stem cell mobilization have better functional outcomes as opposed to patients with a lower mobilization. ... If [MSCs exhaustion syndrome] is true, then a stem cell therapy approach could be feasible. For instance, ex vivo expansion and reinfusion of MSCs from the patient's own or from allogeneic donors, as evidence shows that MSCs are not immunogenic at all, have been already tested in many clinical trials .... In the best case scenario, MSCs therapy could retard the onset of irreversible lesions associated with metabolic syndrome or at least partially improve those already present."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118295/

It is worth watching the prevalence of longevity insurance offerings, as this is a measure of the degree to which the actuarial community and insurance industry believes that increases in human life span will happen in the near future, but that they will not be large. For the insurer, longevity insurance is a bet on earlier than anticipated death: "Most people buy life insurance to protect against the risks of dying too soon. Now, there are new products offering the same protection if you live too long. It's known as longevity insurance, and there's clearly a huge market for it: Life expectancies are on the rise, cushy pensions are on the decline, and most people don't have enough savings to carry them through two decades or more of retirement. This is not lost on insurance companies, which would like you to think about the product as a pension of sorts - albeit one that you have to buy with your own money. ... But what happens if Merck invents the magic pill and we all live until 105? ... Continued improvements in medicine that allow people to live longer could create losses on our individual annuity business. but these would be more than offset by higher gains on the life insurance. ... Still [if] something like that were to happen, 'at some point, capacity might be limited.'" Companies that bet against large increases in longevity are likely to suffer greatly in decades to come - which is unfortunate for the rest of us, because these concerns are large enough to run to the nearest government for a bailout, and thus we all end up paying for collective bad bets.

Link: http://bucks.blogs.nytimes.com/2011/06/28/longevity-insurance-buying-down-the-risks-of-living-too-long/

There should be no such thing as "I don't know what to do with my life." Scratch that statement away and erase it, as it should be "I will aid the development of life extension technology until I do know."

It should be no surprise to anyone that many, or perhaps even a majority of people at any given time have no real idea as to what they want to do with their lives. No vision, no grand dream that captures them, no burning desire to achieve a specific great work. That isn't because they are incapable - far from it, it is because they haven't found their own personal blue touch paper yet. The space of ideas and ideals is vast, and even the most aggressively autodidactic internet-addicted polymath cannot embrace more than a fraction of the sphere of human knowledge. Yet you cannot know your grand vision, the one that resonates with everything your life has led to up until that point, if you never encounter its roots.

Which is where we come back to time. We tell the younger folk that it doesn't matter if they don't know what they want to do with their lives, as that knowledge will come with time. The rituals and mythology that spring from the passage from childhood to adulthood, repeated billions of times over the course of history, are as much about expanding horizons as they are about anything else. In our comparatively wealthy modern society, that process of expansion doesn't have to stop when you stop growing in body - except for the fact that we are all limited by the realities of the human condition, and aging in particular.

Our lives have a timer, and we are all well aware of it, for all that many of us prefer not to think about it at all. The whole structure of life and society revolves around the existence of that timer, as it ticks away the freedom we have remaining in which to find and work on something worthwhile. The rush to find meaning in life? There because we don't have enough time. The need to save for retirement and medical costs? The timer again, ticking away our health and ability to fend for ourselves.

When you cannot see even the first shape of what will be your life's work, and time is ticking away, the best thing you can do is to offer a helping hand to those who work on making more time - scientists, advocates, and others who support research and development of rejuvenation biotechnologies. You can do that at the same time as you search for the cause or idea that truly speaks to you, and it beats slumping back into the grey doldrums that seem to afflict so much of our society: people who never found that fire inside, and who have no time left in which to do so.

You have an option that the older folk of previous generations did not: you can help make more time for everyone, more health, more years, and time enough to find meaning in what you do.

There should be no such thing as "I don't know what to do with my life." Scratch that statement away and erase it, as it should be "I will aid the development of life extension technology until I do know."

It should be no surprise to anyone that many, or perhaps even a majority of people at any given time have no real idea as to what they want to do with their lives. No vision, no grand dream that captures them, no burning desire to achieve a specific great work. That isn't because they are incapable - far from it, it is because they haven't found their own personal blue touch paper yet. The space of ideas and ideals is vast, and even the most aggressively autodidactic internet-addicted polymath cannot embrace more than a fraction of the sphere of human knowledge. Yet you cannot know your grand vision, the one that resonates with everything your life has led to up until that point, if you never encounter its roots.

Which is where we come back to time. We tell the younger folk that it doesn't matter if they don't know what they want to do with their lives, as that knowledge will come with time. The rituals and mythology that spring from the passage from childhood to adulthood, repeated billions of times over the course of history, are as much about expanding horizons as they are about anything else. In our comparatively wealthy modern society, that process of expansion doesn't have to stop when you stop growing in body - except for the fact that we are all limited by the realities of the human condition, and aging in particular.

Our lives have a timer, and we are all well aware of it, for all that many of us prefer not to think about it at all. The whole structure of life and society revolves around the existence of that timer, as it ticks away the freedom we have remaining in which to find and work on something worthwhile. The rush to find meaning in life? There because we don't have enough time. The need to save for retirement and medical costs? The timer again, ticking away our health and ability to fend for ourselves.

When you cannot see even the first shape of what will be your life's work, and time is ticking away, the best thing you can do is to offer a helping hand to those who work on making more time - scientists, advocates, and others who support research and development of rejuvenation biotechnologies. You can do that at the same time as you search for the cause or idea that truly speaks to you, and it beats slumping back into the grey doldrums that seem to afflict so much of our society: people who never found that fire inside, and who have no time left in which to do so.

You have an option that the older folk of previous generations did not: you can help make more time for everyone, more health, more years, and time enough to find meaning in what you do.

Artificial cells are one possible line of future biotechnology; devices built to resemble the body's building blocks, essentially nanomachines constructed of proteins. Here researchers take a modest step in that direction, by developing "a novel method of disguising nanoparticles as red blood cells, which will enable them to evade the body's immune system and deliver cancer-fighting drugs straight to a tumor. ... The method involves collecting the membrane from a red blood cell and wrapping it like a powerful camouflaging cloak around a biodegradable polymer nanoparticle stuffed with a cocktail of small molecule drugs. Nanoparticles are less than 100 nanometers in size, about the same size as a virus. ... This is the first work that combines the natural cell membrane with a synthetic nanoparticle for drug delivery applications. This nanoparticle platform will have little risk of immune response. ... Stealth nanoparticles are already used successfully in clinical cancer treatment to deliver chemotherapy drugs. They are coated in a synthetic material such as polyethylene glycol that creates a protection layer to suppress the immune system so that the nanoparticle has time to deliver its payload. ... today's stealth nanoparticle drug delivery vehicles can circulate in the body for hours compared to the minutes a nanoparticle might survive without this special coating. But in [this latest] study, nanoparticles coated in the membranes of red blood cells circulated in the bodies of lab mice for nearly two days. ... one of the next steps is to develop an approach for large-scale manufacturing of these biomimetic nanoparticles for clinical use. ... Researchers will also add a targeting molecule to the membrane that will enable the particle to seek and bind to cancer cells, and integrate the team's technology for loading drugs into the nanoparticle core so that multiple drugs can be delivered at the same time."

Link: http://www.sciencedaily.com/releases/2011/06/110620161300.htm

From the Technology Review: "The drug rapamycin has been found to reverse the effects of Hutchinson-Gilford progeria syndrome, a fatal genetic disease that resembles rapid aging, in cells taken from patients with the disease. Rapamycin, an immunosuppressant drug used to prevent rejection of transplanted organs, has already been shown to extend life span in healthy mice. Researchers hope the findings will provide new insight into treating progeria as well as other age-related diseases. Skin cells from patients with progeria show a slew of defects: deformities in their membranes, decreased growth, and early death. [Researchers] found that rapamycin could reverse these defects by enhancing the cells' ability to degrade the protein progerin, which accumulates in abnormal amounts in progeria patients. It's not yet clear whether the drug will have similar effects on animals or patients. But progeria researchers are planning a clinical trial of rapamycin. ... Researchers say the findings could be relevant beyond this rare genetic disease. Although accumulation of progerin is associated with progeria, the protein also accumulates in small amounts in normal cells, and may be partially responsible for the aging process."

Link: http://www.technologyreview.com/biomedicine/37916/

As you may know, a range of ways to extend life in nematode worms (such as the common laboratory species Caenorhabditis elegans) involve interfering in the operation of mitochondria. This is also true in a range of other lower animals - mitochondrial operation is apparently strongly coupled to the natural range of longevity enjoyed by a given species. But what are mitochondria? They are a roving swarm of tiny power plants, present inside every cell, and inside each mitochondrion there can be found an array of intricate molecular machinery that gives rise to what is called the electron transport chain. This is a critical component in the process of building stores of chemical energy - in the form of ATP - used to power the operation of the cell. It is alterations in the operation of the electron transport chain that can alter longevity for the better in many species.

A recent open access paper digs into other mechanisms that relate to this link between electron transport chain operation and life span, outlining the discovery of a gene that is necessary for that enhanced longevity:

Mitochondria have long been associated with aging and age-related diseases. Recent research has shown that a slight dampening of mitochondrial function can dramatically increase the lifespan of a wide range of organisms, suggesting that a similar mechanism likely operates in humans. The molecular basis of this observation is largely unknown, however. Uncovering the genes that allow altered mitochondrial function to impact longevity will give us important new insights into how mitochondria affect the aging process and will pave the way for future therapeutic developments aiming to improve healthy aging and to treat age-related diseases.

Here, we used an RNAi screen in the genetic model organism C. elegans, a nematode worm, to uncover how altered mitochondrial function can modulate longevity. We found that in order for mitochondria to affect lifespan, they must communicate with several unique transcription factors in the nucleus. Notably, we discovered that the putative homeobox transcription factor CEH-23, which has not previously been implicated in longevity determination, is able to respond to changes in mitochondrial function and in turn causes an extension in lifespan. ... ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background.

So it looks like some form of programmed response causes the life extension in these methods, and manipulations of the electron transport chain only trigger that response - which is interesting. Not what you might expect, given all the other ways in which mitochondria touch on aging, such as through accumulated damage to their DNA.

A long and fascinating post from Chronosphere details the extensive preparations that go into transporting the body of a cryonics patient for cryopreservation: "Many patients will be remote from the facility where cryoprotective perfusion will be carried out and will be transported by common carrier or private carrier over considerable geographical distances. In some cases it will be possible to move the patient using a specialized transport vehicle with on-going extracorporeal support. In other cases the distances will be sufficiently great that the only realistic option is iced-shipment in the absence of perfusion. It is often necessary to use a commercial air freight service to move the patient from one area of the United States to another (or from one country to another). ... Because of time constraints to get freight loaded rapidly, air freight is often not handled with care by airport personnel. ... Whenever possible, the Transport Technician should supervise the handling of the patient every step of the way, including on and off the aircraft. Due to recent terrorist acts it has become increasingly difficult for the Transport Technician to do this. Until quite recently it was usually easy for the Technician to get access to air freight facilities and the tarmac to supervise loading of the patient onto the aircraft. This is now all but impossible. However, it is still important to accompany the patient to the air freight depot and to emphasize that extra care should be used in handling the patient, and that every precaution should be taken against misrouting."

Link: http://chronopause.com/index.php/2011/06/28/commercial-air-transport-of-the-cryopreservation-patient/

You may recall that composition of cell membranes is strongly correlated to species longevity - the idea being that some membranes are more resistant to the damage of reactive oxygen species than others, and that damage resistance at the cellular level ultimately translates into a longer-lived animal. Here is more on that topic: "This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species(ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated with membrane peroxidizability and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via nontargeted reactions with cellular macromolecules and (ii) modulate signaling pathways that control longevity-assurance mechanisms."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21708248

Type 2 diabetes is the poster child for an avoidable age-related condition: barring the worst of genetic bad luck, calorie restricted, well exercised people will not suffer from type 2 diabetes. But this is, undeniably, an age-related illness. Becoming ever more obese and sedentary will hasten the onset of diabetes into ever earlier years of life, but older obese and sedentary people are still far more likely to suffer type 2 diabetes than are equally overweight and sedentary younger counterparts. So while failing to take care of your health at any age is just another form of self-harm, there are other, less avoidable processes taking place at the level of cells and organs that make older people more vulnerable.

Here is an open access paper that reviews what researchers presently know of the decline of insulin-producing beta cells in the pancreas - which turns out to be not enough, as is still true of so much of our biochemistry. There are changes, cataloged and identified, but the chains of causation for those changes are poorly understood at best.

Type 2 Diabetes and the Aging Pancreatic Beta Cell

An increased incidence of diabetes is observed with age, and there are many possibly reasons for this. One of these is that the beta cell has reduced proliferative capacity and in diabetic individuals this is further confounded by higher rates of beta cell apoptosis. The currently known underlying mechanisms behind the reduction in beta cell proliferation observed with age include reduced expression of cell cycle activators, increased expression of cell cycle inhibitors, reduced pdx1 expression, and increased amylin aggregation. Studying aging in the non-diabetic rodent and human models is currently a developing field; therefore very few broad conclusions can be drawn. Further study in these areas is important as they could indicate targets for preventing or slowing the progression of diabetes with age.

I look on this as a good illustration of why the detailed, tissue by tissue, understand everything approach to repairing aging is doomed to take a very long time indeed. This is but one population of vital cells in one organ, one of the most studied forms of cell in past decades, and the research community remains far from a complete understanding as to how and why they fail with age.

Better strategies to deal with aging exist - such as SENS - and need to gain wider support and adoption. SENS-like approaches work around the challenge posed by the sheer complexity of human biochemistry by focusing on the known common mechanisms of aging, the root causes from which there is good reason to believe all other changes descend. Repairing these root causes is the fast path to the first generation of rejuvenation biotechnology, and that, in my eyes, is the only real shot at building viable interventions in the aging process that will arrive in time to help us.