The average or maximum lifespans of these tortoises aren’t really known, since birth records of the tortoises kept in captivity are sketchy at best, they are often of indeterminate age when they are taken or rescued from the wild. They appear to take around 20 years to become sexually mature and can grow for several decades. It’s even thought that they exhibit negligible senescence, which is to say they don’t really age at all. Their deaths, when they come, are possibly always the result of something other than ‘old age’

Some proof of Jonathan’s extreme age comes in the form of this photo, which shows Jonathan in the year 1900 posing with a Boer war prisoner on the remote island of St Helena:

Read more about Jonathan at dailymail.co.uk…

Resveratrol protects cardiomyocytes from hypoxia-induced apoptosis through the SIRT1-FoxO1 pathway.

Biochem Biophys Res Commun. 2008 Dec 3; PMID: 19059213

Chen CJ, Yu W, Fu YC, Wang X, Li JL, Wang W.

Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.

Loss of cardiomyocytes through apoptosis has been proposed as a cause of ventricular remodeling and heart failure. Ischemia- and hypoxia-induced apoptosis of cardiomyocytes reportedly plays an important role in many cardiac pathologies. We investigated whether resveratrol (Res) has direct cytoprotective effects against ischemia/hypoxia for cardiomyocytes. Exposure of H9c2 embryonic rat heart-derived cells to hypoxia for 24h caused a significant increase in apoptosis, as evaluated by TUNEL and flow cytometry, while treatment with 20muM Res greatly decreased hypoxia-induced apoptosis in these cells. Exposure of the cells to Res (20muM) caused rapid activation of SIRT1, which had a dual effect on FoxO1 function: SIRT1 increased FoxO1’s ability to induce cell cycle arrest, but inhibited FoxO1’s ability to induce cell death. This effect could be reversed by SIRT1 inhibition. Results of our study indicate that Res inhibits hypoxia-induced apoptosis via the SIRT1-FoxO1 pathway in H9c2 cells. This polyphenol may have potential in preventing cardiovascular disease, especially in coronary artery disease (CAD) patients.

Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress.

Free Radic Biol Med. 2008 Nov 5; PMID: 19061950

Zhang L, Jie G, Zhang J, Zhao B.

Epigallocatechin gallate (EGCG), a main active ingredient of green tea, is believed to be beneficial in association with anticarcinogenesis, antiobesity, and blood pressure reduction. Here we report that EGCG extended Caenorhabditis elegans longevity under stress. Under heat stress (35 degrees C), EGCG improved the mean longevity by 13.1% at 0.1 mug/ml, 8.0% at 1.0 mug/ml, and 11.8% at 10.0 mug/ml. Under oxidative stress, EGCG could improve the mean longevity of C. elegans by 172.9% at 0.1 mug/ml, 177.7% at 1.0 mug/ml, and 88.5% at 10.0 mug/ml. However, EGCG could not extend the life span of C. elegans under normal culture conditions. Further studies demonstrated that the significant longevity-extending effects of EGCG on C. elegans could be attributed to its in vitro and in vivo free radical-scavenging effects and its up-regulating effects on stress-resistance-related proteins, including superoxide dismutase-3 (SOD-3) and heat shock protein-16.2 (HSP-16.2), in mutant C. elegans with SOD-3Colon, two colonsgreen fluorescent protein (GFP) and HSP-16.2Colon, two colonsGFP expression. Quantitative real-time PCR results showed that the up-regulation of aging-associated genes such as daf-16, sod-3, and skn-1 could also contribute to the stress resistance attributed to EGCG. As the death rate of a population is closely related to the mortality caused by external stress, it could be concluded that the survival-enhancing effects of EGCG on C. elegans under stress are very important for antiaging research.

As much as this study disappoints me, it would be disingenuous for me to omit it from this blog, and as much as one has to sigh at the possibility of countless hours of research going up in smoke, it is of course helpful if it redirects our energies elsewhere (if it is indeed true).

To summarize the press release, which is unfortunately a bit lacking in details, Dr David Gems from UCL and his colleagues studied the action of ‘key genes’ involved in removing superoxide in C. elegans (nematode worms). They (presumably) upregulated these genes to enhance the worms’ innate anti-oxidative capacities. They found that the lifespans of the worms were ‘relatively unaffected’ by the change.

Which led Dr Gems to say:

One of the hallmarks of ageing is the accumulation of molecular damage, but what causes this damage? It’s clear that if superoxide is involved, it only plays a small part in the story. Oxidative damage is clearly not a universal, major driver of the ageing process. Other factors, such as chemical reactions involving sugars in our body, clearly play a role. A healthy, balanced diet is very important for reducing the risk of developing many diseases associated with old age, such as cancer, diabetes and osteoporosis, but there is no clear evidence that dietary antioxidants can slow or prevent ageing. There is even less evidence to support the claims of most anti-ageing products.”

In the absence of the actual study, I can’t really comment on the science, except to say that I hope they checked their results properly. However, I guess I’ve never heard of a substance that extends lifespan as a result of its anti-oxidant capacity alone. Indeed, if supplementing with anti-oxidants did extend lifespan, one would assume a daily vitamin C would do the trick (it doesn’t). Does this mean there’s no point in trying to quench free-radicals? Well, as Dr Gems says, they’re good for reducing the risks of age-related pathologies, just not the main one – death.

From my limited information, it appears that this study stands in opposition to the recently-reported ‘Universal Theory of Aging‘, which suggests aging is a result of the re-deployment of sirtuins away from DNA regulation to sites of oxidative damage. So, I’m of the opinion that the book is not yet closed on the Free-Radical theory of Aging, and it’s just another case of over-excited scientists jumping the gun.

After all, there is always this study: Extension of murine life span by overexpression of catalase targeted to mitochondria., which one would consider to be more important given that it used a higher organism (mice). I guess the debate will continue to rage for some time yet.

Traditionally, the anti-aging effects of telomerase have been poorly explored because of its unfortunate cancer-promoting activity. Consequently, the researchers genetically engineered cancer-resistant mice by up-regulating their expression of tumor suppressor proteins p53, p16, and p19ARF.

TElomerase Reverse Transcriptase (TERT, or just ‘telomerase’) was additionally overexpressed to observe the anti-aging effects of increasing its concentrations in the cell. It was found that TERT overexpression improved the fitness of epithelial barriers (particularly the skin and the intestine) and produced a systemic delay in aging, as well as an actual extension of the median life span.

Also, the genetically enhanced mice showed a better preservation of both the thickness of the epidermis and of the subcutaneous fat layer compared to the controls. What this means is, if they were humans, one of the main factors that is the cause of the appearance of old age, i.e. subcutaneous fat loss, would be somewhat reduced.

Interestingly, with regard to their lifespans: The mice that had their tumor suppression capabilities enhanced, but lacked TERT enhancement, saw no increase in lifespan. Those mice with both modifications saw a 26% increase in median lifespan. Of these mice, those that did not die of cancer (i.e., those that could be considered to have died of ‘old age’) experienced a 38% increase in median lifespan.

Translated into human terms, this would make living to an age of 110 years commonplace.

All in all, this is a very exciting study that suggests that if we can somehow eliminate the threat of cancer, steps towards markedly slowing the rate of aging are definitely in the pipeline. This is just one of the many fronts on which aging is being gradually defeated by the force of human ingenuity. I’m looking forward to the future developments of this research!

Some brief fundamentals:

What are telomeres?
Inside the nuclei of our cells, DNA doesn’t just sit there in a loose, tangled string. It is highly organized, with several orders of organization that become apparent as it is viewed at an increasing scale. At the smallest level, DNA is wrapped around a disc-shaped protein called a histone octamer. There are many of these histone complexes running along the DNA strand, giving it a ‘beads on a string’ appearance. These ‘beads’ are refered to as ‘nucleosomes’.

Nucleosomes then arrange themselves into fibrils, then the fibrils are super-coiled into chromatin fiber. The chromatin fiber forms loops or ‘domains’ ranging from 30,000-100,000 base pairs in length, which are eventually aggregated to form the highest order structure, the chromosome. It can be thought of as coils upon coils upon coils upon coils, and this is how such a long strand of DNA (around 3 metres in humans) can fit inside the nucleus of a cell.

At the end of each chromosome is where we find the telomere. Telomeres consist of short, repeating, TG-rich DNA sequences. Human telomeres have a variable number of repeats of the sequence 5′-TTAGGG-3′, which can extend for several kilobases.

What causes telomere shortening?
Functional telomeres are essential for continuous cellular proliferation; however, maintaining telomeres of adequate length is problematic for the cellular machinery. For a variety of complicated hypothetical reasons to do with the mechanics of DNA replication, each time the cell divides, the two resulting chromosomes have slightly shorter telomeres than the original.

The average rate of loss is estimated to be around 50-75 base pairs per telomere per cell division.

To compensate for this loss, we have the enzyme telomerase. Telomerase is a multisubunit RNA-containing complex related to viral RNA-dependent DNA polymerases (reverse transcriptases). It is the enzyme responsible for telomere synthesis and thus for maintaining the length of the telomere.

In adult cells, telomerase is inactive or only present at very low levels. It has been suggested that the purpose of this progressive erosion of the telomeres, coupled with the progressive inactivation of telomerase, is to place an upper limit on the number of times a cell can divide, so that cells whose proliferative schedule is corrupt – i.e., tumors – will be automatically limited to a set number of replications, limiting the potential for damage. Of course, cunning as they are, tumors often turn the production of telomerase back on, thereby immortalizing themselves.

Telomere shortening prevents cancer, but promotes aging
Because our cells have an upper limit placed on their proliferative capacity, at some point in time they lose their ability to replicate. As we grow older, the regenerative capacity of our cells deteriorates, and this is considered to be one of the main reasons that we age.

So, we’re faced with a dilemma: If we activate telomerase, we facilitate the unrestricted cellular division that is cancer; if we inactivate it, our life force is doomed to eventually grind to a sad, grey halt.

Fortunately for the mice in the above study, they were genetically engineered to have super tumor-resistant cells.

What are p53, p16, and p19ARF, and how do they prevent tumors?

p53 is a transcription factor that has the following important properties:

• It can activate DNA repair proteins when DNA has sustained damage.
• It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
• It can initiate apoptosis, programmed cell death, if the DNA damage proves to be irreparable.

p16 is a gene that can produce a protein that can interact with and sequester MDM2, a protein responsible for the degradation of p53. So in essence, p16 stops p53 from being destroyed, maintaining adequate levels in the cell.

p19ARF is a mouse protein that also regulates MDM2’s ability to inhibit p53. The absence of the gene that encodes this protein (INK4a) leads to inappropriate cell survival and a higher incidence of cancer.

Reference: Telomerase Reverse Transcriptase Delays
Aging in Cancer-Resistant Mice. Cell 135, 609–622, November 14, 2008

Photo credit: lesliemiperry, Flickr

The study looked at the effects of 1,000 mg/day vitamin C and 800 IU/day vitamin E vs placebo in 396 healthy, non-smoking adults. Participants who started out with CRP levels greater than 2 milligrams per liter (elevated levels) had 34 percent lower levels of CRP when treated with vitamin C compared with placebo. The recommended upper limit for vitamin C supplementation is 2,000 mg/day (although many people exceed this without negative consequences).

They also found a link between obesity and elevated CRP levels, assumedly because obesity represents a state of low-grade, chronic inflammation. In fact, 75% of obese people have elevated CRP levels.

Interestingly, no significant effects due to vitamin E on CRP levels were found.

So, according to this study, we can say that vitamin C supplementation reduces levels of CRP in people with elevated levels. Unfortunately, it’s not really clear whether the levels are reduced as a result of inflammation levels being reduced, or for some other reason. Simply reducing CRP would presumably have no beneficial effect – say, if the mechanism was that excess vitamin C was interfering with CRP synthesis in the liver.

A quick review of the literature, however, only yielded studies suggesting that vitamin C supplementation reduced inflammation by its effect in reducing inflammation biomarkers.

C-reactive protein (CRP)

CRP is produced in the liver and by adipocytes (fat cells). It was discovered as a substance in the serum of patients who were experiencing acute inflammation. It was initially thought to be secreted by pathogens, such as Streptococcus pneumoniae, one of the organisms responsible for pneumonia, because it was elevated in people with this and other diseases, including cancers.

Later, its synthesis in the liver was discovered, and its function as a way for the body to tag damaged cells and microbes that require removal by the body’s defense cells – macrophages – was elucidated.

Chronically high levels of CRP have been associated with risk for diabetes, hypertension, and cardiovascular disease. However, CRP itself is merely an indicator of disease and not a cause of the pathologies it is associated with.

SRT1720 is initially being purported as a treatment for diabetes as it affects glucose metabolism, but its real promise in my and many others’ opinions is its life-extension potential.

I won’t bother reiterating the coverage at this point, rather directing you to a couple of articles that have emerged over the past few days:

• Scientific American: Wine diet in a pill: Mice stay trim and fit on drug
• Wired Science: Next-Generation Longevity Drug Works Mouse Wonders

In the adrenal glands, TElomerase Reverse Transcriptase (TERT) gene expression is reduced as a result of estrogen insufficiency. This was shown to lead to significantly shorter telomeres, compromised cellular proliferation, and adrenal atrophy.

Three weeks administration of estrogen restored TERT gene expression, telomerase activity, and cell proliferation in the estrogen-deficient mice used in the study.

The adrenal glands are an extremely important part of the endocrine system and producers of a variety of hormones in the human body. They are the body’s main source of the catecholamine hormones adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine. They are also devoted to the synthesis of corticosteroid hormones from cholesterol.

Adrenal insufficiency manifests a number of undesirable symptoms, such as frequent dizziness, fainting, incoherence, and loss of brain activity. In addition, reduced sex drive, abdominal weight gain, a higher incidence of respiratory diseases, and a host of other maladies result from the underproduction of adrenal hormones.

This lends weight to the importance of maintaining adequate estrogen levels throughout life and particularly after menopause. Research into more effective Hormone Replacement Therapy (HRT) continues, and should be seriously considered by women fighting tooth and nail against the ravages of time.