The immune system is vital for many reasons. It is not just a barrier against pathogens of all sorts, such as bacteria, fungi, and viruses, but also a watchdog that hunts down and destroys harmful cells, such as those that have entered senescence or are in danger of becoming cancerous. In later life the immune system declines and fails in characteristic ways, partly a consequence of its evolved structure and resource limits, and partly the same general accumulation of damage that affects all cells in the body. The failure of the immune system is important because it contributes to other threads in aging: allowing senescent cells to build up, failing to catch cancers when they can be easily destroyed, and generating ever higher levels of inflammation. This increasing incapacity alongside increasing inflammation is known as immunosenescence or inflammaging.

Here is an open access paper on the subject:

Hallmarks of human "immunosenescence": adaptation or dysregulation?

Is immunosenescence an intrinsic ageing process leading to dysregulation of immunity or an adaptive response of the individual to pathogen exposure? Age-associated differences in bone marrow immune cell output and thymic involution suggest the former. Accepted hallmarks of immunosenescence (decreased numbers and percentages of peripheral naïve T cells, especially CD8+?cells, and accumulations of memory T cells, especially late-stage differentiated CD8+ cells) suggest the latter, viewed as the result of depletion of the reservoir of naïve cells over time by contact with pathogens and their conversion to memory cells, the basis of adaptive immunity.

Thymic involution beginning early in life limits the generation of naive cells such that the adult is believed to rely to a great extent on the naïve cell pool produced mostly before puberty. Thus, these hallmarks of immunosenescence would be markedly affected by the history of the individual's exposure to pathogens, [and] in humans, particularly to infection with CMV.

...

One very striking difference [between industrialized Western populations and those of poorer regions is that in] the "wild-type" situation, all humans are infected with CMV from the age of ca. 2?months on, when they no longer receive only anti-CMV antibody in the mother's milk, but also the infectious virus that has reactivated in the meantime. CMV-negativity is an artifact of civilization, hygiene and decreased breast feeding. Hence, in our pilot study of young and old men in rural Pakistan, all the young were already CMV-positive. As "old" is viewed as [greater than] 50?years in this society, we sought to establish whether age-associated differences in immune phenotypes that we and others had established in older European and US populations were similar in Pakistanis, and whether they manifested earlier in the latter.

We concluded that there were two major differences between the Pakistani population and the historical controls of [subjects from Western, industrialized regions]. One was that we did indeed see age-associated differences in CD8+ T cells earlier in the Pakistanis, and the other was that we saw for the first time in a healthy population that not only the CD8+ subset but also the CD4?+?T cells were affected. This we had otherwise only seen in pathological European populations, eg. those with Alzheimer's. We interpret this to mean that the level of "antigenic stress" in the Pakistani population, old at 50, could indeed be leading to "premature immunosenescence".

Some thoughts on what can be done to reverse some of the declines in the aging immune system - alongside a few concrete results in laboratory animals - can be found a little way back in the Fight Aging! archives.

• Prospects for Immune System Rejuvenation Through Selective Destruction
• Immune System Rejuvenation Achieved Through Targeted Cell Destruction
• Exercise and the Destruction of Age-Damaged Immune Cells

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There are a great many theories of aging, and here is another for the pile from a researcher who leans towards aging as genetic programming rather than aging as accumulated damage: "The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against aging and increase lifespan. ... However, recent tests of the oxidative damage theory, many using the short-lived nematode worm Caenorhabditis elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory [proposes] that aging is caused by hyperfunction, i.e. over-activity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in mortality. ... Here we assess whether the hyperfunction theory is at all consistent with what is know about C. elegans aging, and conclude that it is. In particular, during adulthood C. elegans show a number of changes that may reflect pathology and/or hyperfunction. Such changes seem to contribute to mortality, at least in some cases (e.g. yolk accumulation). ... Our assessment suggests that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain aging in C. elegans."

Link: http://extremelongevity.net/2012/08/09/is-aging-due-to-hyperfunction/

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Progress towards a non-invasive test for Alzheimer's disease: "Reliability and failure to replicate initial results have been the biggest challenge in this field. We demonstrate here that it is possible to show consistent findings. ... [Researchers] measured the levels of 190 proteins in the blood of 600 study participants [including] healthy volunteers and those who had been diagnosed with Alzheimer's disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer's disease, causes a slight but measurable decline in cognitive abilities. A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer's. When those markers were checked against data from 566 people participating in the multicenter Alzheimer's Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide. Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer's. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer's, and full Alzheimer's. ... Though a blood test to identify underlying Alzheimer's disease is not quite ready for prime time given today's technology, we now have identified ways to make sure that a test will be reliable."

Link: http://www.eurekalert.org/pub_releases/2012-08/eu-btf080912.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Progress towards a non-invasive test for Alzheimer's disease: "Reliability and failure to replicate initial results have been the biggest challenge in this field. We demonstrate here that it is possible to show consistent findings. ... [Researchers] measured the levels of 190 proteins in the blood of 600 study participants [including] healthy volunteers and those who had been diagnosed with Alzheimer's disease or mild cognitive impairment (MCI). MCI, often considered a harbinger for Alzheimer's disease, causes a slight but measurable decline in cognitive abilities. A subset of the 190 protein levels (17) were significantly different in people with MCI or Alzheimer's. When those markers were checked against data from 566 people participating in the multicenter Alzheimer's Disease Neuroimaging Initiative, only four markers remained: apolipoprotein E, B-type natriuretic peptide, C-reactive protein and pancreatic polypeptide. Changes in levels of these four proteins in blood also correlated with measurements from the same patients of the levels of proteins [beta-amyloid] in cerebrospinal fluid that previously have been connected with Alzheimer's. The analysis grouped together people with MCI, who are at high risk of developing Alzheimer's, and full Alzheimer's. ... Though a blood test to identify underlying Alzheimer's disease is not quite ready for prime time given today's technology, we now have identified ways to make sure that a test will be reliable."

Link: http://www.eurekalert.org/pub_releases/2012-08/eu-btf080912.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A number of diverse lines of research and development will lead to new technologies that replace or repair organs. The present list looks much as follows:

• Electromechanical and blended biological-electromechanical systems: artificial hearts, prosthetic limbs and eyes, dialysis machines that contain cultured kidney tissue, and so forth.
• Repair of organs in situ using transplanted stem cells or stem cell signaling to spur regrowth that otherwise would not happen.
• Engineering of complete organs from a patient's own cells, such as through bioprinting.
• Decellularization to replace the cells in human donor tissue and organs in order to form patient-matched transplants.
• Xenotransplantation: the use of decellularized organs and tissues from animals, which provide the structure and chemical cues to allow repopulation with the patient's human cells.

A recent article at the Scientist looks at a couple of these lines of work - organ engineering versus xenotransplantation, both of which draw heavily upon the comparatively new techniques of decellularization in order to achieve new and better results, both in the laboratory and for patients in trials:

Today, the organ shortage is an even bigger problem than it was in the 1980s. ... he supply has stagnated despite well-funded attempts to encourage donations, and demand is growing, especially as the organs of a longer-lived population wear out.

Faced with this common problem, Vacanti and Cooper have championed very different solutions. Cooper thinks that the best hope of providing more organs lies in xenotransplantation - the act of replacing a human organ with an animal one. From his time in Cape Town to his current position at the University of Pittsburgh, he has been trying to solve the many problems that occur when pig organs enter human bodies, from immune rejection to blood clots. Vacanti, now at Massachusetts General Hospital, has instead been developing technology to create genetically tailored organs out of a patient's own cells, abolishing compatibility issues. "I said to myself: why can't we just make an organ?" he recalls.

In the race to solve the organ shortage, xenotransplantation is like the slow and steady tortoise, still taking small steps after a long run-up, while organ engineering is more like a sprinting hare, racing towards a still-distant finish line. Most of those betting on the race are backing the hare. Industry support has dried up for xenotransplantation after years of slow progress, leaving public funders to pick up the expensive tab. Stem cells, meanwhile, continue to draw attention and investment. But both fields have made important advances in recent years, and the likely winner of their race - or whether it will result in a draw - is far from clear.

...

Xenotransplants will always have to deal with an immune clash of some degree, so growing an organ that is perfectly matched to a patient would be preferable. The question is whether tissue-engineering technologies will reach that point before genetic engineering enables the first transgenic pig hearts or kidneys to be successfully installed in patients. Sachs says, "I consider xenotransplantation still the nearest-term, best hope for solving the organ shortage, but in the long run, I think tissue engineering will replace it."

There is also the matter of scale. Platt thinks that organ engineering is too costly to meet the needs of everyone waiting for a transplant. "You'd have to turn over the entire GDP of a country to accomplish that," he says. On the other hand, "I could get a pig for a couple of hundred dollars." But Macchiarini argues that organ engineering is in its infancy, and every advance improves efficiency and lowers cost. "What we did in 2008 in 6 months, we can now do in a few weeks," he says. "We do care about getting this to every patient." Vacanti adds that mass-producing artificial scaffolds will make organ engineering even more cost-effective. "When you scale them up, the bulk materials and manufacturing tech are extremely cheap," he says. "I think it's going to be cheaper than growing lots of pigs."

We shall see. The only sure thing in my book is that vigorous competition is good for both speeding progress and producing higher quality solutions. That is just as true in medicine as for every other field of human endeavor.

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http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Efforts continue to correlate longevity with the activity levels of specific genes: "MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. ... We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. ... we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA.

Link: http://dx.doi.org/10.1186/1471-2164-13-353

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