This is because, while the ability to degrade the matrix is extremely important in growth and wound healing, if the processes of synthesis and degradation fall out of balance in favour of degradation, the overall amount of collagen will decrease.

In youth, these processes are in balance, but as we age, the degradative enzyme activity begins to overpower that of synthesis, leading to a loss of skin quality. Other factors that increase MMPs are photodamage and smoking.

In the past, I’ve boosted my skin’s balance in favour of collagen synthesis with isotretinoin, which worked beautifully but has drawbacks that in my opinion make it unacceptable for chronic use (cracking lips, sun sensitivity, etc.). I’ve also heard that the skin’s response to collagen-synthesis stimulating retinoids decreases with age.

So, in theory, one could boost its overall levels by instead interfering with the breakdown of collagen by inhibiting MMPs.

At present, the only MMP inhibitor that’s available readily and cheaply is doxycycline hyclate, an antibiotic often used to combat acne. Apparently, by taking a subantimicrobial dose (i.e., too little to kill bacteria) one can benefit from its anti-MMP activity while minimizing its side effects. Doxycycline is also used in this way in dentistry, where it is used to facilitate healing of the connective tissue in the gums.

There was also a study where doxycycline’s effect on wound healing was investigated because it was suspected it may *interfere* with normal wound healing as a side-effect, but it was instead found that the wounds actually healed either at the same rate or faster.

So, lately I’ve been noticing the accumulation with age and decades of intense sunlight a slight loss of skin elasticity (yes, wrinkles), so I decided to start taking 25mg/day doxycycline for a couple of months and see if this has any effect on the quality of my skin. I’ve taken some ‘before’ photos that highlight the problem, and I intend to compare these with pictures taken in 1 and 2 months to see if I can identify any change.

The literature is at first glance almost entirely free of this kind of experiment, with most papers focussing on doxycycline’s antibacterial and anti-inflammatory effects for the treatment of acne and rosacea. I’m sure there’s a good reason for this that I in my limited capacity don’t have time to dig up, so I’m pressing ahead regardless.

I’ll post the results, including before/after shots and analysis in about a month

Here’s some reading in the meantime:

• Inhibition of matrix metalloproteinases: a new skin care frontier
• Matrix metalloproteinases
• Doxycycline

Essentially, the researchers examined the effect of knocking out the Angiotensin (Ang) II type 1 receptor in a bunch of mice and compared them in various ways to a wild-type control group. The knockout mice lived significantly longer than the controls, and when they looked at the internal organs, they saw that the knockout mice exhibited somewhat less deterioration of their organs and cardiovascular systems.

So marked was the effect on lifespan, that even when all of the wild type mice had died, 17 of the 20 knockout mice remained alive.

The exact reasons for why this mutation caused an increase in lifespan are interesting and discussed in the article, but what interests me is that angiotensin II type 1 receptor antagonists (drugs that interfere with its function) are presently available and in use. AT1 antagonists have been proven to be safe and well-tolerated for chronic use and are used as a key component of modern therapy for hypertension and cardiac failure.

One drug in this category is Losartan, also known as Cozaar. The question is – can angiotensin II type 1 antagonists like Losartan be integrated into a supplementation program for human life extension? What I mean is, should I add this to my ’stack’?

It seems that the most useful drug in this family is Telmisartan, also known as Micardis, due to its much longer half life. Micardis appears to be readily available from your average online pharmacy.

I’ll certainly be looking further into this in the near future.

It’s always good when an old (and therefore out of patent) drug gets fresh life breathed into it, especially when it’s touted as a potential new anti-aging therapy. Clioquinol was used as an antifungal and antiprotozoal up until the ’60s when it was implicated in an outbreak of Subacute Myelo-Optic Neuropathy (SMON) in Japan and discontinued. This was despite the absence of a proper investigation into whether it was actually the cause.

Now, researchers at McGill University in Canada have discovered a possible mechanism for clioquinol’s recent implication with lifespan-extension. Dr. Siegfried Hekimi et al. from McGill’s Department of Biology reports that it interacts with the CLK-1 protein, potently inhibiting its activity.

Clioquinol has been shown recently in animal models to reverse the progression of Alzheimer’s, Parkinson’s, and Huntington’s diseases.

“Because clock-1 affects longevity in invertebrates and mice, and because we’re talking about three age-dependent neurodegenerative diseases, we hypothesize that clioquinol affects them by slowing down the rate of aging,” says Dr Hekimi.

CLK-1, which exists in yeast and other eukaryotes, has a human homolog COQ7 and it’s responsible for the biosynthesis of ubiquinone in the mitochondrial and other membranes.

Ubiquinone is a co-factor in a variety of cellular redox processes, including mitochondrial electron transport, and it’s often involved in processes that produce reactive oxygen species (ROS).

Defects of the gene that encodes CLK-1 apparently slow down a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors, and aging (see Felkai et al., 1999).

Dr. Hekimi speculates that metal chelation may be involved in the effect, given that clioquinol is a metal chelator, meaning that it binds to metal ions in the cell, inactivating them or leading to their removal. Whether or not this is true remains to be seen…

Regardless, it’s great to see that an effective and cheap inhibitor of CLK-1 has been found. Next we’d like to see animal tests, especially as to whether it extends maximum lifespan. If successful, my guess is that more potent versions that are new and patentable will be investigated and hopefully one day brought to market. In the meantime, I don’t know if I’m brave enough to start taking clioquinol, I’ll look further into it, but I suspect I will be waiting on further results before diving in.

Refs:

• Eurekalert! press release
• Pubmed abstract
• Felkai,S, Ewbank,J.J, Lemieux,J, Labbé,J.-C, Brown,G.G. and Hekimi,S “CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans”, EMBO Journal 18, 1999

The team, headed by Professor Gerald I. Shulman, investigated substances known as N-acylphosphatidylethanolamines, or NAPEs, which are synthesized and secreted into the blood by the small intestine after fatty foods are eaten. When rats and mice were regularly injected with NAPEs, they experienced suppressed appetites and reduced their food intake.

It is believed NAPEs reduce the activity of hunger neurons in the brain and stimulate satiety neurons. I know, this is a rather obtuse description, but what it means is that NAPEs act on the brain itself to suppress appetite as opposed to some other physiological effect, like causing the stomach to contract or whatnot.

While NAPEs have not yet been tested in humans, that’s the very next thing on the agenda for the researchers at Yale, and who knows – a NAPE-based anti-fat pill could be prescribed to you in the not too distant future.

The findings will be published in the 26 November 2008 issue of Cell and were brought to my attention through a Eurekalert! press release.

A study from the American Academy of Neurology reports that despite evidence that increased IGF-I helps reduce beta-amyloid plaques in the minds of mice, the IGF-I stimulating drug MK-677 did not help humans given the drug for one year.

J.J. Sevigny of Merck Research Laboratories in North Wales, PA said:

This work suggests that targeting this hormone system may not be an effective approach to slowing the rate of Alzheimer’s disease progression. Importantly it challenges the common theory that hormones may attack beta-amyloid plaque in the brain and builds on the body of clinical evidence for Alzheimer’s disease as we seek to develop more effective treatments.”

Thanks to Eurekalert! for the press release.