There are multiple mechanisms that contribute to the progression of insulin resistance with aging. The most significant contributions seem to stem from excess fat tissue and a sedentary lifestyle, and the metabolic consequences of those choices. (Yes, being fat is absolutely a choice for nearly all people, and one that they could begin to reverse at any point in time by changing the way they live their lives). Avoiding diabetes is a very plausible goal if you keep in shape - but even the most fit of elderly folk suffer some degree of rising insulin resistance and metabolic dysfunction as a consequence of the accumulating biological damage of aging. There is the insulin resistance you can escape, and then there is the insulin resistance you can't.

One line item that crops up when discussing the intersection of exercise, inflammation and insulin resistance, and the course of aging is NF-κB - one of the many machine parts in the cell that seems to have a finger in every pie by virtue of being involved in the process of manufacturing other machine parts. Manipulating NF-κB can extend life in flies, and has beneficial effects in other laboratory animals. Here, a couple of recently published papers look at NF-κB as a regulator of insulin resistance - avoidable and otherwise - and possible target for old-style drug development.

Endothelial NF-κB in Obesity and Aging: Is Endothelial NF-κB a Master Regulator of Inflammation and Insulin Resistance?

Insulin resistance is a major characteristic of type 2 diabetes and develops in multiple organs including skeletal muscle, liver, adipose tissue, and heart. Insulin resistance is caused by obesity and therefore establishes an important causal relationship between obesity and type 2 diabetes. Insulin resistance also develops in aging, but this process is less well understood.

Blockade of the NF-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Lifespans

To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice [that] exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although [the] mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetically-induced.

...

In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged lifespan. These anti-aging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity and aortic up-regulations of mitochondrial sirtuin-related proteins. ... Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome as well as for anti-aging strategies.

At the present pace, by the late 2020s researchers will be able to tell you exactly why, how, and how much common lifestyle choices impact your future health and life expectancy. But it's worth noting that this won't help you live any longer - you could make the same smart choices now as you would if presented with a much thicker bundle of scary evidence. The 80/20 of present day widely available health practices is easy to achieve, after all: calorie restriction and regular exercise. None of this, however, gets us any close to true rejuvenation biotechnology. For that, we need more resources heading towards the work of the SENS Foundation and their allies in the research community.

If you think that telomere length is a secondary marker of aging and health, then it makes perfect sense that exercise would lengthen telomeres. There is ample evidence to show that average telomere length, while declining with age, is somewhat dynamic in response to circumstances, at least in the white blood cells examined by most present day research: "Leukocyte telomere length (LTL) is a potential indicator of cellular aging; however, its relation to physical activity and sedentary behavior is unclear. The authors examined cross-sectionally associations among activity, sedentary behavior, and LTL among 7,813 women aged 43-70 years in the Nurses' Health Study. Participants self-reported activity by questionnaire in 1988 and 1992 and sedentary behavior in 1992. Telomere length in peripheral blood leukocytes, collected in 1989-1990, was measured by quantitative polymerase chain reaction. ... For total activity, moderately or highly active women had a 0.07-standard deviation (SD) increase in LTL compared with those least active. Greater moderate- or vigorous-intensity activity was also associated with increased LTL ... Associations remained after adjustment for body mass index. ... Although associations were modest, these findings suggest that even moderate amounts of activity may be associated with longer telomeres, warranting further investigation in large prospective studies."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22302075

As you might imagine, exercise affects the behavior of muscle stem cells: "researchers determined that an adult stem cell present in muscle is responsive to exercise, a discovery that may provide a link between exercise and muscle health. The findings could lead to new therapeutic techniques using these cells to rehabilitate injured muscle and prevent or restore muscle loss with age. Mesenchymal stem cells (MSCs) in skeletal muscle have been known to be important for muscle repair. ... Since exercise can induce some injury as part of the remodeling process following mechanical strain, we wondered if MSC accumulation was a natural response to exercise and whether these cells contributed to the beneficial regeneration and growth process that occurs post-exercise. ... The researchers found that MSCs in muscle are very responsive to mechanical strain. They witnessed MSC accumulation in muscle of mice after vigorous exercise. Then, they determined that although MSCs don't directly contribute to building new muscle fibers, they release growth factors that spur other cells in muscle to fuse and generate new muscle, providing the cellular basis for enhanced muscle health following exercise. ... Next, the group hopes to determine whether these cells contribute to the decline in muscle mass over a person's lifetime. Preliminary data suggest MSCs become deficient in muscle with age. The team hopes to develop a combinatorial therapy that utilizes molecular and stem-cell-based strategies to prevent age-related muscle loss."

Link: http://news.illinois.edu/news/12/0206muscle_MarniBoppart.html

As I mentioned the other day, there are more economic benefits to enhanced human longevity than just the obvious ones. Some of these benefits emerge from systematic changes in the interactions and relationships that make up society: the willingness to consider longer time horizons changes the way in which people value all sorts of things, both in the present and for the future. If fifty years from now is someone else's problem in your eyes, you are unlikely to be a good steward of fifty-year bonds - but if you are going to be alive, vocal and very much in the picture five decades from now, then the way in which you look at these things becomes completely different. You can substitute forests, farmland, houses, familial relations, companies, or a range of other entities for the fifty-year bonds there: we humans instinctively put a value on everything, and there's nothing wrong with that. The more that people value their relationships, possessions, future earnings, and a hundred other line items, the more willing they are to invest in maintaining these tangible and intangible entities.

This incentive to invest and improve is important, because short-termism is the road to ruin in all things economic - and everything that we do is in the general sense an economic decision. All wealth and civilization is built upon the move away from short-termism, to depart from the practice of strip-mining the present because you believe you are unlikely to benefit from the future. As the expectancy of human life increased over the past few centuries, so the time horizons of our ancestors broadened, and they became more likely to take actions that increased wealth: planning for the long term, investing in technology and research, trading rather than war, and building rather than tearing down.

A longer and healthier life is a good thing for individuals, but it is also positive for the whole society. This speech will give a quick description of positive political, economical and sociological aspects of a world with a largely delayed senescence: lower health costs, lower level of violence, higher level of happiness...

As a species, we are of course very much still mad, illogical barbarians by any absolute measure. But we are less so than now than in past generations - less violent at least, and more compassionate, although still just as deluded when it comes to a great many other topics, such as belief in the existence of dubiously benevolent sky gods. A great deal of that progress can be attributed to the changing incentives and values brought by increased longevity - and then the compound interest of small gains, amassed year after year.

Osteoporosis is a pervasive issue in the old, and potential methods for reversing its effects are welcome: scientists have "developed a novel technique to enhance bone growth by using a molecule which, when injected into the bloodstream, directs the body's stem cells to travel to the surface of bones. Once these cells are guided to the bone surface by this molecule, the stem cells differentiate into bone-forming cells and synthesize proteins to enhance bone growth. ... There are many stem cells, even in elderly people, but they do not readily migrate to bone. Finding a molecule that attaches to stem cells and guides them to the targets we need is a real breakthrough. ... The researchers made use of a unique hybrid molecule, LLP2A-alendronate ... The researchers' hybrid molecule consists of two parts: the LLP2A part that attaches to mesenchymal stem cells in the bone marrow, and a second part that consists of the bone-homing drug alendronate. After the hybrid molecule was injected into the bloodstream, it picked up mesenchymal stem cells in the bone marrow and directed those cells to the surfaces of bone, where the stem cells carried out their natural bone-formation and repair functions. ... Twelve weeks after the hybrid molecule was injected into mice, bone mass in the femur (thigh bone) and vertebrae (in the spine) increased and bone strength improved compared to control mice who did not receive the hybrid molecule. Treated mice that were normally of an age when bone loss would occur also had improved bone formation, as did those that were models for menopause." This is an example of the future of stem cell medicine - more about directing and altering stem cells in the body to create in-situ effects than providing new cells or growing tissue for transplant.

Link: http://www.eurekalert.org/pub_releases/2012-02/uoc--rdm020312.php

Enhancing autophagy, the cellular housekeeping processes that recycle damaged components and proteins, is one of the possible approaches under investigation for treating a range of age-related conditions and modestly slowing aging. The accelerated aging condition progeria is caused by malformed lamin A, an important structural protein in cells. An accumulation of bad lamin A is something that also occurs in normal aging, albeit to a much lesser degree. Here, researchers propose turning autophagy to remove the damaged lamin A: "Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts ... Importantly, rapamycin treatment does not affect lamin C protein levels ... Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool to eliminate progerin."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22297442

It is not unreasonable to regard a cell as a machine that is constantly rebuilding itself - organelles and protein machinery are constantly torn down and replaced. It is also not unreasonable to regard tissue as a collection of cells that is constantly rebuilding itself: cells destroy themselves or are destroyed by watchdog systems, and new cells are created to replace them. This sort of thing happens rapidly indeed in some parts of the body, such as the blood and stomach lining, but there are portions of your nervous system where cells will never be replaced under normal circumstances - the cells you were born with are the very same cells you have now.

These long-lived cells are the most vulnerable to forms of age-related damage involving build up of metabolic waste products, and the related slow failure in the ability of cells to recycle their own damaged components. There is no fallback to replacing cells wholesale in this case, or at least not in our species, so long-lived cells must forge ahead and struggle to do their job no matter how damaged they are. The existence of these cells is a good argument for the need for in situ repair technologies, able to reverse damage and remove other hinderances in order to allow long-lived cells to regain their vigor and function - goals that are hard to attain with the present generation of cell replacement technologies emerging from the field of regenerative medicine.

Now consider this: it may be the case that some of the individual vital proteins in the machinery of long-lived cells are also never replaced. Some of your complex individual proteins, important cogs and gears in important cells, might be as old as you are. The very same sorts of concern about vulnerability surface here as well. Here is news of research in rats:

The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism. ... ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. Unlike other proteins in the body, ELLPs are not replaced when they incur aberrant chemical modifications and other damage.

...

The fundamental defining feature of aging is an overall decline in the functional capacity of various organs such as the heart and the brain. This decline results from deterioration of the homeostasis, or internal stability, within the constituent cells of those organs. Recent research in several laboratories has linked breakdown of protein homeostasis to declining cell function. ... Most cells, but not neurons, combat functional deterioration of their protein components through the process of protein turnover, in which the potentially impaired parts of the proteins are replaced with new functional copies. Our results also suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs.

Given how much longer humans live in comparison to rats, it may be that there are no proteins in the human body that never turn over. But I wouldn't be surprised to find that the situation for old humans is exactly the same as described above for old rats.

An advance in the methodologies of nerve repair: "scientists believe a new procedure to repair severed nerves could result in patients recovering in days or weeks, rather than months or years. The team used a cellular mechanism similar to that used by many invertebrates to repair damage to nerve axons. ... We have developed a procedure which can repair severed nerves within minutes so that the behavior they control can be partially restored within days and often largely restored within two to four weeks. If further developed in clinical trials this approach would be a great advance on current procedures that usually imperfectly restore lost function within months at best. ... nerve axons of invertebrates which have been severed from their cell body do not degenerate within days, as happens with mammals, but can survive for months, or even years. The severed proximal nerve axon in invertebrates can also reconnect with its surviving distal nerve axon to produce much quicker and much better restoration of behaviour than occurs in mammals. ... Severed invertebrate nerve axons can reconnect proximal and distal ends of severed nerve axons within seven days, allowing a rate of behavioural recovery that is far superior to mammals. In mammals the severed distal axonal stump degenerates within three days and it can take nerve growths from proximal axonal stumps months or years to regenerate and restore use of muscles or sensory areas, often with less accuracy and with much less function being restored. ... The team described their success in applying this process to rats ... The team were able to repair severed sciatic nerves in the upper thigh, with results showing the rats were able to use their limb within a week and had much function restored within 2 to 4 weeks."

Link: http://www.eurekalert.org/pub_releases/2012-02/w-npr020112.php

To what degree does nuclear DNA damage contribute to aging? That remains a debated question. Here, researchers show that, at least in immune cells, there are perhaps more forms of large DNA damage than thought in the old: "researchers compared the DNA of identical (monozygotic) twins of different age. They could show that structural modifications of the DNA, where large or small DNA segments change direction, are duplicated or completely lost are more common in older people. The results may in part explain why the immune system is impaired with age. During a person's life, continuous alterations in the cells' DNA occur. The alterations can be changes to the individual building blocks of the DNA but more common are rearrangements where large DNA segments change place or direction, or are duplicated or completely lost. ... The results showed that large rearrangements were only present in the group older than 60 years. The most common rearrangement was that a DNA region, for instance a part of a chromosome, had been lost in some of the blood cells. ... Rearrangements were also found in the younger age group. The changes were smaller and less complex but the researchers could also in this case show that the number of rearrangements correlated with age. ... We were surprised to find that as many as 3.5 percent of healthy individuals older than 60 years carry such large genetic alterations. We believe that what we see today is only the tip of the iceberg and that this type of acquired genetic variation might be much more common. ... The researchers believe that the increased number of cells with DNA alterations among elderly can have a role in the senescence of the immune system. If the genetic alterations lead to an increased growth of the cells that have acquired them, these cells will increase in number in relation to other white blood cells. The consequence might be a reduced diversity among the white blood cells and thereby an impaired immune system." Compare that with the other explanations for reduced diversity that involve persistent and pervasive viruses like CMV.

Link: http://www.eurekalert.org/pub_releases/2012-02/uu-itr012612.php

Immunotherapy is a very broad and active field: there are a great many strategies presently under development, and in various stages of maturity. All aim at making the immune system do the heavy lifting of finding and destroying specific unwanted cells, cellular machinery, and other biochemicals in the body. This is actually the immune system's evolved purpose, more or less, and so adjusting it to destroy new targets without causing harmful side-effects is a plausible near term technology. Thus there are large segments of the life science community looking into immunotherapies for cancer, immunotherapies to destroy some of the harmful aggregates that build up between cells with age, and so forth.

One of the presentations given at last year's SENS5 conference was a look at turning the immune system against harmful aggregates of tau protein - as seen in Alzheimer's disease, for example, but which happens in all brains to some degree:

One of the perils of aging is the accumulation of various protein/peptide aggregates throughout the body, some of which are associated with toxicity. In several age-related disorders, aggregates of certain amino acid sequences are much more prominent than under normal conditions, and define the disease. Harnessing the immune system has emerged in recent years as a promising approach to treat these conditions. My laboratory has worked in this field targeting the amyloid-β peptide, the prion protein, the tau protein, and more recently the islet amyloid polypeptide. The focus of my talk will be on our tau immunotherapy studies. We have shown in tangle mouse models that active or passive immunizations clear pathological tau aggregates from the brain with associated functional benefits.

A thought to leave you with: the more we see the research community working on immunotherapies for age-related conditions, there more likely it becomes that significant investments will be made into reversing the decline of the immune system. The effectiveness of these therapies to a degree depends on the effectiveness of the immune system, and that progressively fails with age - having first generation therapies in the market will ensure that there exists a strong incentive to improve those therapies, and one of the most obvious ways to do that is to rejuvenate the immune system in elderly patients.

From the Wall Street Journal, a good example of the way in which much of present day research gravitates towards applications that patch over end-stage consequences of disease rather than addressing root causes and prevention: "Research into how iron, copper, zinc and other metals work in the brain may help unlock some of the secrets of degenerative diseases like Alzheimer's and Parkinson's. Iron and copper appear to accumulate beyond normal levels in the brains of people with these diseases, and a new [study] shows reducing excess iron in the brain can alleviate Alzheimer's-like symptoms - at least in mice. ... Research into the complicated, invisible roles these metals play in brain diseases has lagged behind study of the more-visible proteins that are damaged or clump together in the brains of Alzheimer's and Parkinson's sufferers. But better understanding metals' role in the brain could help shed light on a range of medical conditions and might offer a new route for developing treatments. ... [Researchers] examined the amount of iron in the brains of mice that were bred unable to produce the tau protein, which helps stabilize the structure of neurons. Tau damage is associated with Alzheimer's and Parkinson's. As the mice aged, they suffered symptoms similar to people with both diseases, including impaired short-term memory, and also exhibited an accumulation of iron in their brains. When the researchers gave them a drug removing excess iron, the symptoms reversed. This means normally functioning tau is necessary for removing iron in the brain ... The finding bolsters previous research showing that bringing down iron may be a path to new treatments. ... An accumulation of iron in neurons seems to be a final end-stage event in neurodegeneration, whether it be Alzheimer's or Parkinson's, [or] any [condition] related to tau abnormalities."

Link: http://online.wsj.com/article/SB10001424052970204740904577192901072611524.html

Researches find another way in which the brain declines with age: "New findings [reveal] a novel mechanism through which the brain may become more reluctant to function as we grow older. ... researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" - this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. ... The [researchers] identified that in the aged brain it is more difficult to make hippocampal neurons generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurons. ... Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down ... Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." You might compare this with past work on potassium channels and memory in aging.

Link: http://www.sciencedaily.com/releases/2012/02/120201105124.htm

Are you presently working on a life science or medical degree? Are you interested in advancing aging and longevity science - research that aims to extend the healthy human life span and reverse the causes of age-related disease? Do you want to intern this summer at the SENS Foundation, one of the most important young non-profits in the world?

In the summer of 2012, the Academic Initiative will bring as many as three students to the SENS Foundation Research Center in Mountain View, California to participate in SENS research for three months. These students will receive monthly stipends and, if they are not local to the San Francisco Bay Area, a credit towards airfare.

Undergraduate, graduate, and medical students may apply, as may students who have graduated immediately prior to the summer. After an initial selection process, the most promising candidates will be interviewed over the phone by the SENS researchers they would work with. Each major research program at the Research Center will limit itself to one intern, such that each intern will be working on a different project and will be selected by different researchers. It will be important for applicants to have prior lab experience, and more experienced applicants are more likely to be accepted than relatively inexperienced ones.

The application is available online here. Applications are due by March 31, 2012. The most promising applicants will be interviewed in April. As always, if you have any questions, you can contact us.

Chances to work on the foundations of world-changing research programs don't wander past the window every day. Beyond that, the SENS Foundation is a great place for younger researchers - people who are serious about longevity science and have a genuine interest in advancing the state of the art - to come into contact with a network of more experienced peers, fundraisers, and advocates that will serve well in later years. Connections are what makes the world go round, and certainly what advances careers and opens doors.

The extracellular matrix (ECM) surrounds and supports cells, both structurally and in a range of other ways, such as by mediating cell signalling. With age, however, the ECM changes for a variety of reasons - it is damaged by the actions of senescent cells, for example. This has consequences, such as on the capacity of stem cells to maintain tissue. Here is a review paper: "Aging is characterized by reduced tissue and organ function, regenerative capacity, and accompanied by a decrease in tissue resident stem cell numbers and a loss of potency. The impact of aging on stem cell populations differs between tissues and depends on a number of non cell-intrinsic factors, including systemic changes associated with immune system alterations, as well as senescence related changes of the local cytoarchitecture. The latter has been studied in the context of environmental niche properties required for stem cell maintenance. Here, we will discuss the impact of the extracellular matrix (ECM) on stem cell maintenance, its changes during aging and its significance for stem cell therapy. ... It is concluded that a remodeled ECM due to age related inflammation, fibrosis or oxidative stress provides an inadequate environment for endogenous regeneration or stem cell therapies." The question of whether an old body can fully benefit from stem cell therapies continues to arise - eventually the stem cell research community will have to start addressing the damage of aging in order to assure the performance of their therapies when treating the old.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22285947

Autophagy is very important to long term health, and shows up again and again as a pivotal part of the way in which various genetic manipulations and lifestyle choices can improve health and extend life. Here is a good article that delves into the mechanisms of autophagy and the present limits of scientific understanding: "Cells live longer than their internal components. To keep their cytoplasm clear of excess or damaged organelles, as well as invading pathogens, or to feed themselves in time of nutrient deprivation, cells degrade these unwanted or potentially harmful structures, and produce needed food and fuel, using a process they have honed over millions of years. Known as autophagy, this catabolic process involves the selection and the sequestration of the targeted structures into unique transport vesicles called autophagosomes, which then deliver the contents to lysosomes where they are degraded by lytic enzymes. ... Experimental evidence indicates that autophagosome biogenesis is probably a very complex process on several levels, including its regulation in response to different cellular and environmental cues, and the factors governing the choice of membrane sources. Is there any therapeutic value in determining the origin of the autophagosomal membranes? We think that elucidating this process could ultimately provide new drug targets for the treatment of diseases that can be alleviated or cured by the activation of autophagy, including specific muscular dystrophies, persistent infections, and neurodegenerative disorders (ataxias, Huntington's, and Parkinson's diseases). Understanding the sources and processes by which the autophagosome's lipid bilayers are delivered will undoubtedly reveal critical new proteins and articulate their functions, allowing researchers to pinpoint specific parts of the pathway."

Link: http://the-scientist.com/2012/02/01/the-enigmatic-membrane/