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Feb 24
RAAS Schematic
Image via Wikipedia

It seems every few weeks there is a new scientific paper reporting the benefits of resveratrol or resveratrol-like drugs (e.g SRT1720), which is believed to mediate its effect through SIRT1 (there was a new SIRT1 paper last week in the prestigious science journal - though I didn’t think it was that important). And the popular press are quick to cover every new resveratrol paper.

But I need to remind the readers that while resveratrol was demonstrated to improve life span of mice on a high fat unhealthy diet (Baur et. a., 2006), when tested on mice on a normal diet resveratrol did not extend life span (Pearson et. al., 2008) (also see my coverage of this paper here). However, in the second study the mice did not start taking resveratrol until 12 months of life (middle age) so it is an open question if it would work if started earlier. Though, there are several companies that have a vested interest in reporting positive life span effects, and in theory they have been running the experiments since before 2006 so I wonder why we have not seen positive results published (see here)?

While, there is another clinically approved drug for hypertension that targets the renin-angotensin system (RAS) has now been shown twice to extend the life span of mice.The RAS is involved in blood pressure, water balance, and therefore influences the cardiovascular system. This system releases angiotensin which gets converted into angiotensin II (Ang II) which mediates its effect by acting on the Ang II type 1 receptor. I first became aware of this field of research in a 2009 paper that targeted this system genetically.

Genetic manipulation led to increased life span:

Benigni et. al., 2009 manipulated the RAS by disrupting one of the receptors for Ang II (Atgr1a receptor). The mice with this receptor knocked out had less vascular and cardiac age induced damage. Additionally, in the kidneys more mitochondria were observed as well as an increase in NAMPT and SIRT3. But most importantly the animals with the disrupted Atgr1a receptor lived on average 26% longer.

The researchers give evidence that the manipulation was not simply a result of calorie restriction (well known to increase life span) as both groups weighed the same and consumed the same amount of food.

Clinically used drugs for the RAS also increases life span:

More interesting is that Ang II receptor antagonistic drugs (e.g. Losartan, Valsartan, Irbesartan) which are already use in humans to help with hypertension and cardiac failure (Remuzzi et. al., 2002) also appears to increase life span (as well if they targeted the RAS system earlier in the pathway - see below).

Basso et. al., 2007 tested an ACE inhibitor enalapril (an Angiotensin Converting Enzyme inhibitor) and losartan, which blocks (antagonist) the Ang II receptor (angiotensin II receptor antagonist). They tested these two approaches to inhibit the RAS in rats on a normal chow diet. The animals that were in the treated group started receiving one of the two drugs starting at the time of weaning.

Consistent with the previous paper both groups that were given drugs to block the RAS lived statistically longer; the losartan group lived 19.3% longer and the enalapril group lived 21.4% longer than the control group. In this case the enalapril group did weigh less that the controls, however the losartan group weighed the same as the controls.

And as you would expect with inhibiting the RAS the treated groups also had healthier cardiovascular system in their old age.

What I found interesting even though I try to ready all longevity papers somehow I had missed this RAS story, which looks quite intriguing. On the other hand I am constantly bombarded by the resveratrol story.

Take home message:

Drugs that are fairly widely prescribed (ACE inhibitors, and Ang II receptor antagonists) appears to extend the life span of rats by roughly 20%, even when fed a normal diet. This is further corroborated by genetic manipulation of the RAS via knocking out a Ang II type 1 receptor.

On the other hand we have the reseveratrol drug(s) we always hear about in the high profile scientific journals and popular press and to date they are only reported to increase life span in high fat fed obese mice (the animals taking resveratrol did not become obese despite the diet), with no effects on animals fed a normal diet.

However, we do not know if inhibiting the RAS would improve life span if the ‘treatment’ started at a more reasonable real world  time frame - say what would equate to a 25-30 year old human.

I wonder if we will start hearing about an underground movement of people taking ACE inhibitors or something like losartan, an angiotensin II receptor antagonist?

Now you might say we could just look at all the people that have taken these drugs over the years and retrospectively see if they extend the human life span - however you must remember the people currently taking them already have an underlying cardiovascular problem. In this case we might not see any positive effects compared to the ‘normal’ population without any  cardiovascular complications. Until ‘healthy’ people start taking them - which I am not recommending - we will not know the answer.

Additionally, I will warn you that both ACE inhibitors and angiotensin II receptor antagonists (e.g. lorsartan) like almost all drugs have reported adverse effects. However, it appears that the adverse effects of angiotensin II receptor antagonist seem relatively minor - but for any drug you must take serious caution and technically under the supervision of a licensed doctor.

4 Responses

  1. CC Says:

    A sudden thought hit me: can we assume that old mice die of the same reasons as us - stroke, cancer, some organ failure…
    Hm…what else can they die of… not many eh? But they do have a stronger immune system than humans, I imagine.
    If some drug makes mice live longer, can I assume that this drug reduces the chance of stroke, cancer, etc?

  2. Ward Says:

    CC,

    from my knowledge tumors (benign and malignant) are the leading cause of death in rodents. And rodents are actually quite resistance to cardiovascular diseases. Researchers usually use a combination of genetically ‘prone’ animals and a high fat diet to study cardiovascular disease. That is why the use of a cardiovascular targeted treatment, as discussed in this post, to improve life span in a ‘regular’ rodent is in someways even more impressive.

  3. Jason Utterman Says:

    Interesting post. It’s amazing that more people haven’t heard about this. Wonder why? What is it about Res. that makes it the biggest story going that hasn’t happened w/ this alternative?

  4. Ward Says:

    Jason,

    good question. I am not sure why we mostly hear about resveratrol - or I could only wildly speculate. I see that you are interested/advertise resveratrol. I have nothing against the potential use of resveratrol (though the jury might still be out on the overall results - especially if not overeating) but I think we shouldn’t bet all our research dollars on one compound.

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