There are any number of techniques under development that allow individual cells to be destroyed provided that you can distinguish them from their neighbors: the challenge is in finding characteristic differences in the cells you want destroyed, such as cancer cells or senescent cells. Most of the efforts aimed at producing targeted cell destruction therapies are taking place in the cancer research community, but senescent cells accumulate with age and contribute to degenerative aging - they must also be destroyed. Unfortunately good ways to target senescent cells are somewhat lacking. Candidate mechanisms are emerging, however, and here is another of them:

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, [the] detection of senescent cells remains difficult due to the lack of specific biomarkers. ndeed, most determinants of cellular senescence, such as the upregulation of p53, p16Ink4a, p21WAF/CIP1 or SASP-associated cytokines, are not exclusively observed in senescence, but can also occur in other types of stress responses. In addition, alterations like SAHF or DNA-SCARS formation are frequently observed, but not necessarily a mandatory feature or exclusive to senescent cells.

The current gold standard for the detection of senescence is the so-called senescence-associated β-galactosidase (SA-β-Gal) activity. Although SA-β-Gal has been first suggested as a distinct enzyme, its activity is derived from lysosomal β-Gal encoded by the GLB1 gene. β-Gal is an accepted marker of senescence, but its reliability and specificity have been questioned, as a positive β-Gal reaction has also been detected in human cancer cells that were chemically induced to differentiate, or upon contact inhibition. Moreover, several cell types, such as epithelial cells and murine fibroblasts generally show a weak β-Gal staining.

In the present study, we investigated several lysosomal hydrolases for their suitability as senescence markers and identified α-fucosidase, a lysosomal glycosidase involved in the breakdown of glycoproteins, oligosaccharides and glycolipids, as a novel biomarker for senescence. We demonstrate that α-fucosidase is upregulated [in] all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Our results suggest that detection of α-fucosidase might be a highly valuable biomarker for senescence in general and in particular in those cases where SA-β-Gal activity fails to properly discriminate between senescent- and non-senescent cells.

Link: http://www.landesbioscience.com/journals/cc/article/24944/?show_full_text=true

Progress towards a therapy for the rare accelerated aging condition progeria continues. It remains unclear as to whether the mechanisms responsible for progeria exist in normal aging to a level that is in any way significant. Progeria is caused by malformed prelamin A, and tiny amounts of broken prelamin A can be found in old tissues - but it would really require a therapy for progeria that addressed the issues with prelamin A to easily find out whether this has any meaningful contribution to normal aging.

The classical form of progeria, called Hutchinson-Gilford Progeria Syndrome (HGPS), is caused by a spontaneous mutation, which means that it is not inherited from the parents. Children with HGPS usually die in their teenage years from myocardial infarction and stroke.

The progeria mutation occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus. The target enzyme, called ICMT, attaches a small chemical group to one end of prelamin A. Blocking ICMT, therefore, prevents the attachment of the chemical group to prelamin A and significantly reduced the ability of the mutant protein to induce progeria. "We are collaborating with a group in Singapore that has developed candidate ICMT inhibitor drugs and we will now test them on mice with progeria. Because the drugs have not yet been tested in humans, it will be a few years before we know whether these drugs will be appropriate for the treatment of progeria."

"The resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process. The children develop osteoporosis, myocardial infarction, stroke, and muscle weakness. They display poor growth and lose their hair, but interestingly, they do not develop dementia or cancer." [The researchers are] also studying the impact of inhibiting ICMT on the normal aging process in mice.

Link: http://www.eurekalert.org/pub_releases/2013-05/uog-ptf051413.php

There are all sorts of good reasons to avoid becoming fat. Excess fat tissue is linked to an increased risk of all the common diseases of aging, and correlates well with a shorter life expectancy and higher lifetime medical expenditures. Fat tissue creates higher levels of chronic inflammation and alters the signaling environment in the body, causing a wide range of changes. Here is another of them:

Having too much body fat makes arteries become stiff after middle age, a new study has revealed. In young people, blood vessels appear to be able to compensate for the effects of obesity. But after middle age, this adaptability is lost, and arteries become progressively stiffer as body fat rises - potentially increasing the risk of dying from cardiovascular disease. The researchers suggest that the harmful effects of body fat may be related to the total number of years that a person is overweight in adulthood. Further research is needed to find out when the effects of obesity lead to irreversible damage to the heart and arteries, they said.

Researchers [scanned] 200 volunteers to measure the speed of blood flow in the aorta, the biggest artery in the body. Blood travels more quickly in stiff vessels than in healthy elastic vessels, so this allowed them to work out how stiff the walls of the aorta were using an MRI scanner. In young adults, those with more body fat had less stiff arteries. However, after the age of 50 increasing body fat was associated with stiffer arteries in both men and women. Body fat percentage, which can be estimated by passing a small electric current through the body, was more closely linked with artery stiffness than body mass index, which is based just on weight and height.

"We don't know for sure how body fat makes arteries stiffer, but we do know that certain metabolic products in the blood may progressively damage the elastic fibres in our blood vessels. Understanding these processes might help us to prevent the harmful effects of obesity."

Link: http://www.sciencedaily.com/releases/2013/05/130515085333.htm

Therapeutic cloning or somatic cell nuclear transfer are names given to a method of producing embryonic stem cells from a patient's own cells. These embryonic stem cells could then be used to generate cells of any type as a basis for regenerative therapies. Making the process work has proven to be challenging, however, both from a technical point of view and thanks to misguided attempts to make it illegal. In recent years the focus shifted towards work on induced pluripotent stem cells instead, but a research group now claims success in the original goal:

Scientists [have] successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness. The technique used [is] a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual's DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced. To solve this problem, the [researchers] studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method. The key to this success was finding a way to prompt egg cells to stay in a state called "metaphase" during the nuclear transfer process. Metaphase is a stage in the cell's natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

Link: http://www.eurekalert.org/pub_releases/2013-05/ohs-ort051313.php

Women tend to live longer than men, and there are any number of competing explanations as to why this is the case. They range from risk of mortality relating to lifestyle choices to evolutionary selection operating on the male role in reproduction to various differences in biochemistry that exist between the genders. That the female immune system ages more slowly shouldn't be terribly surprising - but it might be cause or consequence.

Women's immune systems age more slowly than men's, [and] the slower decline in a woman's immune system may contribute to women living longer than men. Researchers looked at the blood of healthy volunteers in Japan, ranging in age between 20 and 90 years old; in both sexes the total number of white blood cells per person decreased with age. The number of neutrophils decreased for both sexes and lymphocytes decreased in men and increased in women. Younger men generally have higher levels of lymphocytes than similarly aged women, so as aging happens, the number of lymphocytes becomes comparable.

Looking in more detail it became apparent that the rate in decline in T cells and B cells was slower for women than men. Both CD4+ T cells and NK cells increased with age, and the rate of increase was higher in women than men. Similarly an age-related decline in IL-6 and IL-10 was worse in men. There was also a age-dependent decrease in red blood cells for men but not women.

"The process of aging is different for men and women for many reasons. Women have more oestrogen than men which seems to protect them from cardiovascular disease until menopause. Sex hormones also affect the immune system, especially certain types of lymphocytes. Because people age at different rates a person's immunological parameters could be used to provide an indication of their true biological age."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=131061&CultureCode=en

Amyloids are solid masses that form in tissues as a result of misfolded proteins. The amount of amyloid increases with age, perhaps due to a failure of mechanisms that keep the levels of damaged or misfolded proteins under control, and this is thought to cause harm and contribute to degenerative aging. In most cases researchers are still lacking a full understanding of the mechanisms involved, however. At the very least having solid clumps and fibrils present where they shouldn't exist can disrupt tissue integrity or even cause larger scale issues such as clogging blood vessels.

One approach to removing amyloid involves the use of the immune system. Immune therapies direct immune cells to attack and break down a specific target, and much of the innovation in their use as a therapy to remove amyloid is happening in the Alzheimer's research community. That condition is associated with amyloid beta, but we can hope that any successful therapies will prove adaptable to other forms of amyloid and thus applicable to human rejuvenation.

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics.

Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.

Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.

Link: http://www.immunityageing.com/content/10/1/18/abstract

Ames dwarf mice lack growth hormone and as a consequence live much longer than their peers. Here the biochemistry of this lineage is considered in light of the membrane pacemaker hypothesis of aging, which suggests that the degree of resistance to oxidative damage in cell membranes is a driving factor in determining longevity. Thus similar species with different proportions of more resistant and less resistant molecules making up their cell membranes have different life spans. Is it possible that this can happen within a species thanks to genetic engineering of the sort that produced the Ames dwarf mouse lineage?

Membrane fatty acid (FA) composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of ageing" proposes that animals which cellular membranes contain high amounts of polyunsaturated FAs (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and further oxidative damage. It remains to be shown, however, that long-lived phenotypes such as the Ames dwarf mouse have membranes containing fewer PUFAs and thus being less prone to peroxidation, as would be predicted from the membrane pacemaker hypothesis of ageing.

Here, we show that across four different tissues, i.e., muscle, heart, liver and brain as well as in liver mitochondria, Ames dwarf mice possess membrane phospholipids containing between 30 and 60 % PUFAs (depending on the tissue), which is similar to PUFA contents of their normal-sized, short-lived siblings. However, we found that that Ames dwarf mice membrane phospholipids were significantly poorer in n-3 PUFAs. While lack of a difference in PUFA contents is contradicting the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived mice provides some support for the membrane pacemaker hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed most for causing oxidative damage. By comparing tissue composition between 1-, 2- and 6-month-old mice in both phenotypes, we found that membranes differed both in quantity of PUFAs and in the prevalence of certain PUFAs. In sum, membrane composition in the Ames dwarf mouse supports the concept that tissue FA composition is related to longevity.

At some point a research group will find a way to alter only membrane constituent molecules and no other factors in laboratory mice, which should go some way towards quantifying the effect on aging and longevity. The challenge with using any of the well known long-lived lineages of mice is that many aspects of their metabolism are different - it is difficult to point to any one of those and talk about how important it may or may not be to extended longevity given the presence of the others.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23640425

Levels of the essential amino acid methionine in the diet appear to be involved in generating the beneficial effects of calorie restriction on health and longevity. Some portion of the resulting changes in the operation of metabolism is based on sensing low levels of methionine. It is thus possible that humans might obtain benefits comparable to those generated by calorie restriction from a sensibly constructed low-methionine diet with a normal calorie intake. The research in support of this supposition is still sparse in comparison to that for calorie restriction, however.

It was first reported in 1993 that rats subjected to a diet restricted in methionine (MR) enjoyed comparable life spans to rats that were on caloric restriction (CR). In the first experiments, methionine was reduced to ⅕ its normal level in the diet, and growth of the rats was severely stunted. We can't live entirely without methionine - the body would not be able to make any proteins at all. Restricting methionine is likely to have impacts on growth, health, and wellbeing that are as yet unstudied in humans. Rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. In one experiment where methionine was severely restricted but not eliminated entirely, ⅕ of the mice died, and the other ⅘ went on to live longer than control mice.

Here's a clue about why methionine is special. The instructions for making proteins is coded into DNA, via the genetic code, which specifies words of 3 DNA letters, each corresponding to one of the 20 amino acids. The genetic code also contains "punctuation", instructions to start and stop. The "start codon" is also the word for methionine. Every chain of amino acids that the body constructs begins with methionine. No methionine - no protein synthesis. A shortage of methionine means that the body is inhibited in making every kind of protein. More genes are expressed (more proteins synthesized) as the body grows older. Perhaps methionine restriction is putting a brake on this production of extra proteins that are not produced when we're young, and that contribute to aging.

Methionine restriction in practice involves eating foods that are low in methionine. Though all protein has methionine, some protein sources are much lower in methionine than others. All animal sources (including milk and especially eggs) are high in methionine. So a methionine-restricted diet is a vegan diet, not just any vegan diet, but a subset of vegan protein sources. There appear to be no general rules. For example, almonds are a good source of low-methionine protein, but Brazil nuts are terrible. Even a strict vegan diet would only reduce methionine intake by about 1/2. Extrapolating from the rodent experiments, we may need to reduce by ~ 3/4 before crossing a threshold where benefits kick in.

Link: http://joshmitteldorf.scienceblog.com/2013/05/13/could-cutting-this-one-nutrient-make-you-live-longer/

When it comes to evolutionary influences on longevity, the evidence supports the idea that species with a high mortality rate due to external causes (e.g. being eaten) will tend to be short-lived. There is no evolutionary pressure to develop the biological mechanisms that will lead to longer reproductive lives if near all individuals are killed comparatively early in life. This study is a novel way to add further supporting evidence to this point of view:

Evolutionary hypotheses for ageing generally predict that delayed senescence should evolve in organisms that experience lower extrinsic mortality. Thus, one might expect species that are highly toxic or venomous (i.e. chemically protected) will have longer lifespans than related species that are not likewise protected. This remarkable relationship has been suggested to occur in amphibians and snakes.

First, we show that chemical protection is highly conserved in several lineages of amphibians and snakes. Therefore, accounting for phylogenetic autocorrelation is critical when conservatively testing evolutionary hypotheses because species may possess similar longevities and defensive attributes simply through shared ancestry. Herein, we compare maximum longevity of chemically protected and nonprotected species, controlling for potential nonindependence of traits among species using recently available phylogenies.

Our analyses confirm that longevity is positively correlated with body size in both groups which is consistent with life-history theory. We also show that maximum lifespan was positively associated with chemical protection in amphibian species but not in snakes. Chemical protection is defensive in amphibians, but primarily offensive (involved in prey capture) in snakes. Thus, we find that although chemical defence in amphibians favours long life, there is no evidence that chemical offence in snakes does the same.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23638626

Some degree of human longevity is genetic rather than the result of environment and lifestyle choice; researchers have guessed that perhaps 25% of variations are genetic, but this is hardly a firm number. It appears to be the case that survival at extreme old age is more influenced by genetic variations than it is in early old age, for example. Given that some predisposition to longevity is thus inherited, it isn't surprising to find that risk levels for specific conditions of aging also correlate with familial longevity:

Based on comparisons of people in their 90s, their spouses, siblings, children and their children's spouses, researchers found that the offspring of people with exceptional longevity were about 40 percent less likely than peers to be cognitively impaired between ages 65 and 79. "It's not necessarily that these individuals never become cognitively impaired, but what it seems like is that there is a delayed onset of cognitive impairment."

For the new study, the researchers used data on cognitive impairment from 1,870 people who are part of the Long Life Family Study, which includes volunteer participants in New York, Massachusetts, Pennsylvania and Denmark. The study included 1,510 people with a family history of longevity and 360 of their spouses, but for this study, researchers used information on just the volunteers who were 89 years old or older when they were recruited.

Overall, the researchers found that about 6 percent of the volunteers' children were cognitively impaired between ages 65 and 79 years old, compared to 13 percent of their spouses and about 11 percent of their cousins. Among the study's long-lived older generation, participants were just as likely to be cognitively impaired by about age 90 as their siblings or spouses. "These families seem relatively protected, but once they reach extreme old age - say after 90 (years old) - their rates of cognitive impairment become comparable."

Link: http://www.reuters.com/article/2013/05/06/us-family-dementia-idUSBRE9450VL20130506