It is well known that caloric restriction to 25-20% the usual basal metabolic requirement extends lifespan across multiple species. There are some data showing consumption of polyphenol antioxidants also extends lifespan in some species.

In the current experiment researchers tested the hypothesis that combining both caloric restriction and antioxidant supplementation would have an additive effect.

The researchers performed survival analysis on a group of 148 mice. Twelve mice served as controls and 68 mice were placed into one of two treatment groups.

The first treatment group were fed an alternate day diet; ad lib feeding alternated with 24 hour fasts. This is a form of caloric restriction. The second treatment group received the same alternate day diet but in addition were fed a mixture of plant polyphenols. This was specifically a mixture of blueberry, green tea, and pomegranate extracts. In particular the mouse feed contained 2% blueberry extract, 115 ppm Sunphenon (epigallocatechin gallate; EGCG), and 0.3% pomegranate powder replacing corn starch.

The results showed that the calorie-restricted rats as expected lived significantly longer than the control animals. However, it was also found that the polyphenol plus caloric restriction group lived longer than the caloric restriction alone group (33.5 versus 31.5 months average).

Using molecular biological techniques the scientists were also able to show that the addition of polyphenols reduced inflammatory pathways.

The authors conclude “our study is the first to demonstrate that polyphenols,when used in conjunction with an intermittent feeding DR protocol, can enhance the longevity-promoting effects of that DR protocol (at least in mice). The underlying mechanism appears to involve reduction of cell stress and inflammation-related activity, some of which seems to be a byproduct of DR itself. In the absence of definitive clinical trials that address the health benefits of DR–polyphenol combinations, our data may have practical relevance for humans seeking to engage in health-promoting behaviors.”

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These properties may explain the evidence from prior research that coffee reduces risk of diabetes and Parkinson’s

In the current issue of the New England Journal of Medicine the results of a large prospective study was published looking at the effect of coffee on all causes of death.

The researchers examined the subjects of the AARP-Health study, a group beginning at ages 50 to 71 and including more than 400,000 men and women followed for over 5,000,000 person-years.

In the first analysis it appeared that coffee drinkers were more like to die during the study period.  However it was observed that many coffee drinkers also smoked cigarette.  When cigarette smokers were excluded from the analysis it was found that coffee drinking actually reduced the death rate.

Death rate was similar in persons who drink one or less coffee per day to non drinker.  For those who drank  one cup death rate was reduced by 6%, for two to three cups death rate was reduced by 10%, and for four to five cups death rate was reduced by 12%.  In those who drank six or more cups death rate was reduced by 10% versus non coffee drinkers.

Drinking coffee was associated with reduced rate of nearly all the leading causes of death.  ”Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer,” wrote the authors.

Though the association between drinking coffee and reduced mortality was firmly statically significant, the authors rightly point out it cannot be proven from this data that the coffee was the cause of the benefit.

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Good evidence has already been reported that taking daily aspirin reduces general cancer risk and specific risk of colorectal cancer.

By targeting molecular pathways involved in inflammation aspirin may reduce both the genesis of cancer as well as its likelihood of spreading.

Now new research shows this remarkable benefit of aspirin can be applied to melanoma, the deadliest form of skin cancer.

The incidence of melanoma is rising and is highest in whites, with an annual incidence of 30 cases per 100,000.

This study followed a cohort of nearly 60,000 subjects enrolled in the Womens Health initiative over an 11 year period.  In this group of post-menopausal women, 25% took aspirin daily.

Overall 548 people developed melanoma during the study. Statistical analysis revealed the likelihood of developing melanoma was reduced by 24% in those who were taken aspirin.  No effect was seen for subjects who took regular non-steroidal anti-inflammatories other than aspirin.

Furthermore, the longer the duration of aspirin use, the stronger the cancer-reducing effect.

“We found that any use of aspirin was associated with a lower risk of melanoma overall, but also offered greater protection with greater duration of use,” said Carol Gamba, a study author.

http://www.medpagetoday.com/MeetingCoverage/SID/32684

Scientists in Spain were successful in using gene therapy to extend the lifespan of mice.

They created a viral DNA vector in which the gene for telomerase was inserted into the virus shell. The virus was then injected into middle age mice (average one year old) and elderly mice (average two years old.)

Telomerase is the enzyme responsible for maintaining the length of a cell’s telomere. These are strings of DNA at the caps of chromosomes which get shorter with each cell division. Once they are wound down to nothing, the cells can no longer divide. By adding exogenous telomerase to the mice cells, theoretically it would prevent senescence and extend lifespan.

Telomerase is normally only expressed at birth and disappears in adulthood.

After the viral transfection the middle aged mice lived an average of 24% longer, and the elderly mice lived an average of 13% longer.

Equally important, there was no increase in cancer gene in the genetically treated mice, and they remained healthy during their additional lifespan.

This study “shows that it is possible to develop a telomerase-based anti-ageing gene therapy without increasing the incidence of cancer”, the authors affirm. “Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage”, they add.

Reference

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Now that genome wide association studies are inexpensive and commonplace, more and more genes are being found inked to extreme longevity.

These analyses are important because they show which genes account for extended lifespans.  Knowing which genes are involved and how they play their roles will allow us to intervene and artificially prolong our lifespans.

The latest study looked specifically for snp variations within genes that “regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals.” In particular variations that were statistically more likely to occur in centenarians as compared to younger controls were sought.

Specifically 78 persons with a median age of 98 from Italy were compared to 76 controls. Two gene variants were found to be more likely in the long-lived cohort. “SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated…with longevity,” wrote the authors .

Those genes write the authors “are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging.”

These two variants add to a a growing list of gene variants that increase the likelihood of achieving an extremely long lifespan.

Reference (http://www.ncbi.nlm.nih.gov/pubmed/22576335)

The angiotensin-renin system plays a role in several key physiological functions including maintenance of blood pressure.  The effect is mediated by a cell surface receptor called the angiotensin receptor.

Studies in mice have shown that disruption of the analogous human receptor in mice extends lifespan.

In the current study, the authors hypothesized that certain variants of this receptor called AGTR1 may be linked to extreme human longevity, especially if the mutations lead to reduced activity.

To find out if there were any association, the scientists analyzed a library of single nucleotide polymorphisms (snp) within or near the AGTR1 gene in a group of Italian centenarians and 376 younger controls.  They identified two snps in the gene promoter region which were linked to longevity.

Next they looked to see if this if these polymorphisms were linked to longevity in a Japanese cohort of 598 semi- and super-centnearians and 422 controls.

This analysis confirmed one particular snp rs275653 was linked to extreme longevity with a high odds ratio of 3.57.

Furthermore in an in-vitro experiment they went on to demonstrate that persons homozygous for the minor allele (G) of this snp has less angiotensin receptors in their circulating white cells and tended to have lower blood pressure.

They conclude “these findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.”

Reference: http://www.ncbi.nlm.nih.gov/pubmed/22569962

It is well recognized that regular aerobic exercise is beneficial to health. There is ample evidence that running in particular may extend lifespan. However some data suggests excess exercise may increase mortality.

Ultramarathon running involves distances greater than 26 miles, sometimes 50 to 100 or more miles at a time, and can surely be considered extreme.

It surprised fans and exercise enthusiasts when True was found dead, and we have awaited the results of his autopsy. They were made available today and the full report is at the link below.

The pathologist found the only abnormality was True’s heart was dilated. In particular his left ventricle was mildly dilated and thickened. There was no evidence of blockage or significant narrowing in any of the coronary arteries; he did not have a heart attack. There was no evidence of trauma such as a fall causing his death.

The coroner concluded it is likely True suffered an exercise -induced cardiac arrhythmia that caused his death. The abnormal rhythm it was concluded occurred due to the structural changes found of his left ventricle.

It is unclear if continued and repeated ultramarathon running caused the changes found in True’s ventricle and led to his death, though it is a distinct possibility.

Full Autopsy Report

The current trial was undertaken as researchers point out “the mechanisms underlying natural variation in lifespan and ageing rate remain largely unknown.”

They did an analysis of genome-wide protein expression in two groups of fruit flies, a wildtype group and a group that were bred to have long lifespans.  The long lived fruit flies were bred to be resistant to starvation (SR).  That correlated to their long lives  as mediated by caloric restriction

The idea was to see what proteins were differently expressed in normal lifespan and long lifespan flies.  The analysis was done at middle age and late life.

Normal lifespan flies revealed upregulation “in expression of genes associated with reproduction, stress and immune response as they aged.”  The long lived flies however showed less variation with age.
The team discovered that genes genes “involved in stress responses were generally higher expressed in SR flies and were characterized by smaller increases in expression with age as compared with
those in controle (C) flies.”

These findings fit with the generaliy idea thgat increasing resistence to oxidative stress tends to increase lifespan.

“Overall, our results contribute to the understanding of the
mechanisms underlying natural variation in lifespan and ageing rate,” conclude the authors.

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Naked mole rats are a unique rodent that have lifespans of over 30 years, more than 10 fold the lifespan of typical rodents.

Recently the genome of the naked mole rat has been sequenced, and researchers continue to work extensively with the animal to discover reasons for its profound longevity.

Indeed any learnings gleaned from this animal could lead to advances in human longevity.

New research is a breakthrough of sorts, it reveals an important ingredient for why the animal live so long.

Proteosomes are cellular organelles or machines that function to break down and recycle damaged proteins within cells.  As cells live proteins are created and then damaged through oxidative stress.  Damaged proteins for one thing cause cells to dysfunction.  They also may aggregate into clumps which can damage or kill the cell.  Protein damage is a major underlying cause of aging.

It is important for cells to detect and destroy damaged proteins.  They do so through the ubiquitin proteasome system which tags defective proteins with ubiquitin molecules and then degrades them in the proteasomes.

In the current stud the researchers compared the activity and composition of the proteasomes of naked mode rats to those of  regular mice.

They discovered the naked mole rats “had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions.”

They also found “the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous,” in the naked mole rats and “that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults.”

Taken together these findings prove “proteasomes in this species are primed for the efficient removal of stress-damaged proteins.”

“Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life,” they conclude.

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The function and fate of our cells are in large part under the control of our genes.  As we being to unravel the effects of various genes on the process of longevity it becomes very important to develop way to control them.

For example some genes may allow for longer lifespans.  If an individual possesses a version of that gene which is linked to shorter lifespans, it would be useful to manipulate that gene’s functions.

Indigestible or injectable drugs aren’t always the answer, they may not be able to get in cell nuclei and affect the action of certain genes or their transcription.

Scientist have developed an exciting new method to control gene function, from outside the body.

The scientist created antibody-coated iron oxide nanoparticles that bind to a receptor that sit on the cell membrane.  This receptor, TRPV1, is a temperature -sensitive ion channel.  It deforms in warm temperature, allowing calcium to diffuse into the cell.

The researchers injected these nanoparticles into mice who also had a genetically modified gene that produces insulin in response to increasewd intracellular calcium.

After injection of the nanoparticles the mouse were exposed to a magnetic field.  The magnetic field could penetrate deeply into the tissue, and increased the temperature of the nanoparticles.  After 30 minutes of exposure to the magnetic field, a measurable drop in the blood glucose level could be seen, proving the particles were exerting a local effect on the cell.

This experiment was created as a proof of concept, not for clinical utility.  It shows however that genetic activity with in cells could be modified by remote control.

http://www.nature.com/news/remote-controlled-genes-trigger-insulin-production-1.10585