My theme the last few weeks has been the signals that trigger the body’s self-destruction with age. The easiest to target are molecules that circulate in the blood. Last week, I covered a few that decrease in blood concentration as we age, and that cripple our defenses. This week, I’ll talk about signals that increase as we age, and that activate self-destruction. There are two principal mechanisms of active self-destruction: inflammation and apoptosis=cell suicide. Both mechanisms are important to the healthy functioning of the body. Inflammation is our first defense against invading pathogens. Apoptosis elimnates diseased and cancerous cells before they can become a problem. But in old age, both are co-opted for self-destruction. Healthy tissues in the body are destroyed by apoptosis, and inflammation leads to arterial damage and heart disease, DNA damage and cancer.
The blood signals, too, are have helpful roles earlier in life, but turn traitorous with age.
Two weeks ago, I listed some protective hormones that are down-regulated with age. In this column, I review some hormones and other signals in the blood that rise with age, and contribute to weakness, loss of function and the diseases of old age.
The pro-inflammatory hormone NFkB was first recognized in the 1940s as a risk factor for cancer. Circulating NFkB increases with age, and it is hard to imagine any benefit to the body from this increase. Last May, the laboratory of Dongsheng Cai at Einstein Med School reported that NFkB is secreted by the hypothalamus — a tiny endocrine gland embedded within the brain, which is known as the clock that controls the daily rhythm of wake/sleep cycles. (More speculatively, the hypothalamus also controls the timing of development and, by extension, aging as well.) Cai was able to shorten life span in mice with extra NFkB, and to lengthen life span (10% increase in maximum life span) by inhibiting NkB.
One of the least-understood aspects of ageing is its coordinated and stereotyped progression in all organ systems. Although researchers have long suspected that the brain orchestrates systemic ageing, compelling evidence of this in mammals has been lacking. Furthermore, we have had no clear understanding of how ageing is affected by inflammation, which is a hallmark of age-related diseases such as diabetes, cardiovascular disease, arthritis and Alzheimer’s disease. In this issue, Zhang et al.1 (page 211) help to make this connection by documenting the integration of inflammatory responses with systemic control of ageing by the hypothalamus — a part of the brain that controls growth, reproduction and metabolism*. [Ref]
Smad proteins are circulating transcription factors. In other words, they are a way that a central command in the body can send a signal through the blood and affect which proteins are transcribed from DNA and manufactured in the peripheral cell.
Smad3 affects creation of new cells which is necessary not just for healing but for keeping muscles healthy and strong. Stem cells in the muscles are called satellite cells, and these are activated every time we exercise to renew and strengthen the muscles.
In aging muscle cells, P-Smad3 increases and holds back the cells’ regenerative power. In vitro studies show that satellite cells can be rejuvenated by reducing P-Smad3. [Ref]
Wnt is a signal from outside of the cell that affects gene transcription inside the cell nucleus, and thus has a powerful, general effect initiated from the outside. It’s not a single protein, but many that effect signaling by the same pathway, with different results. (cancer and insulin resistance fr overexpression…) Wnt is overexpressed in cancer cells
One of the most dynamic and innovative aging labs in the world is run by Irina and Michael Conboy at UC Berkeley. I have previously cited them in connection with parabiosis experiments. The Conboys reported back in 2007 that Wnt signaling changes with age (in mice) in ways that inhibit healing and muscle regeneration. Unfortunately, it’s not as simple as “too much Wnt”, because Wnt is not a single hormone but a whole family of signals. [follow-up ref; another ref]
Transforming Growth Factor-beta proteins are multifunctional cytokines (fancy name for a signaling molecule), secreted by numerous cell types. They are capable of signaling to virtually every cell type and broadly control cell proliferation, differentiation, apoptosis, inflammation and scarring in various tissues [Ref]. TGF-β may contribute to too much apoptosis and too little stem activity as we age. The Conboy lab, writing about TGF-β and Wnt:
The results shown here argue against the notion of systemic TGF-β1 endocrine activity and strongly suggest that TGF-β, released by the known process of platelet activation during sera collection, inhibits satellite cell responses in vitro. These findings also suggest that young sera may contain a functional and natural decoy of TGF-β1, or a competitor of TGF-β1 signaling pathway (either endocrine or released by platelets). Lastly, our results demonstrate that Wnt antagonizes, rather than synergizes with TGF-β1-mediated satellite cell response inhibition. [Ref]
…in other words, we have more TGF-β as we get older, and its activity is inhibited when we are younger. TGF-β plays a role in inactivating stem cells, which we need for repair and rebuilding.
LH and FSH
Luteinizing Hormone and Follicle-Stimulating Hormone have their best-known role in the female menstrual cycle. Men have much less than women at all ages. But surprisingly, both these “gonadotropins” increase with age. What are women doing with extra menstrual hormones after they stop menstruating? In fact it is now accepted that high levels of FSH are programmed from the pituitary (brain) as women approach menopause, and that FSH is part of the hormonal signal that initiates menopause.
Back in 1998, Jeff Bowles published an evolutionary hypothesis that LH and FSH were signals that induce aging and purposefully increase mortality in both men and women. Remarkably, a good deal of circumstantial evidence has accumulated since that time in support of Bowles’s idea.
Female mice that overexpress FSH receptor age prematurely. [Ref]
In women, high FSH is associated with bone loss and osteoporosis, and also with growth of fat cells and weight gain.
In men, high FSH is associated with enlarged prostate and with prostate cancer. (The prostate is one source, secreting FSH.) High (age-adjusted) FSH is associated with an increase in all-cause mortality in men. In middle-aged males, high FSH is associated with muscle pain and increased frailty.
There is a literature of antibodies against the gonadotropins (LH and FSH) going back at least to 1934. Anti-gonadotropins are used to treat sex-associated cancers, and here is a clinical trial that is trying antigonadotropins as an Alzheimer treatment. I am not aware of anti-aging therapies based on blocking the action of FSH and LH, but this would not be difficult to accomplish, and I think the experiment is well worth trying.
Cortisol is the opposite of inflam-aging. Cortisol damps the body’s immune response, making it more tolerant. And yet, cortisol increases as we age (more in women than men), and there are reasons to believe that the results are not good for us.
Cortisol provides the trigger that causes the Pacific salmon’s body to self-destruct after it has returned to fresh water and spawned. Cortisol increases sugar in the blood, part of the insulin resistance of metabolic syndrome. Cortisol levels rise with chronic stress. Cortisol is associated with age-related memory decline, with depression and dementia.
Cushing’s Syndrome is the name given to a constellation of symptoms associated with over-exposure to cortisol, and many of these symptoms sound like “normal aging”: thinning of the skin, rubber tire around the waist, sleep disorders, baldness in men, high blood pressure and a tendency toward osteoporosis.
Drugs that block cortisol receptors are known, but are not in common use.
P53 promotes apoptosis, which is programmed cell death. It is important for eliminating diseased cells and suppressing cancer. But as we age, we have too much p53, and many non-cancerous cells begin to commit suicide, with the result that we lose healthy tissue in the muscles and, even more important, neurons in the brain.
P53 does not circulate in the blood, and in this sense does not belong in the present list. It is produced endogenously in each cell. The amount of p53 (and most other proteins) is regulated by a balance between transcription and degradation. Transcription is the process of reading a DNA gene into messenger RNA, which travels to a ribosome, where its instructions are translated, 3 by 3, into a sequence of amino acids that makes a unique protein. Degradation is managed by first tagging of proteins targeted for destruction using the label molecule ubiquitin. A protein with several ubiquitin tags is recognized by the cell and dragged to the nearest proteosome for recycling.
In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. [hfrom Armando Rivera-Malo in Google Books]
If there is too much p53 late in life, this is executed at the level of the cell, but it happens in response to (yet unidentified) blood-borne signals that carry directives from the brain.
Homocysteine is a variant of an amino acid used as a basic protein building block. It is a small molecule. Increased amounts of homocysteine in the blood are a risk factor for CV disease. Folic acid (a B vitamin) can reduce homocysteine in the blood. But whether the association is causal is controversial [Ref – No; Ref – Yes]
Homocysteine’s health risks are thought to come from deterioration of endothelial cells in the linings of blood vessels. This damage can be reduced by dietary supplementation with curcumin (the anti-inflammatory agent in the Indian spice-root turmeric).
Sex hormones decline with age. There is a lot of data on hormone replacement therapy in women (estrogen and progesterone), and less but also considerable data on testosterone replacement in aging men. Different studies produce different results, and interpretations are contentious. Are sex hormones a mortality risk, or a protection? This is a big topic, and I’m going to have to defer it to another day.
The Bottom Line
There are several known blood signals that promote age-related destruction and disease, and probably many more that are not yet known. Already we know enough to be able to target these signals with anti-bodies and other molecules that block their action. What are we waiting for?
I recently discovered your blog, and I’ve been reading it with great interest during a couple of days.
I’ve never been very interested in CR, since low carb has worked fine for me in terms of general health. I have a couple of questions for you:
a) Keeping the caloric intake, and increasing the caloric expenditure, for instance through exercise, leads to a caloric deficit. This would be equivalent in terms of longevity to a normal CR diet?. For instance, forgetting damaging effects of stressful exercise, Michael Phelps consuming tons of calories and zero fat in the body is in a similar situation as members of CRsociety?.
>> I don’t believe in the whole “caloric balance” paradigm. For example, your low carb diet may keep you far thinner than a high-carb isocaloric equivalent. See my post on “getting less from your food“.
>> There are differences between losing weight with exercise and losing weight by restricting calories. Studied in detail by Luigi Fontana here and here. The long-term effects of CR might be better, but the short-term effects of exercise are much better, and exercise but not CR helps with osteoporosis. Fontana himself keeps very slim with an exercise-based regimen.
b) Is it possible to have a CR diet without feeling awful hunger and miserable?. A life thinking of food can’t be good.
>> Response to diet is very individual, and you have to experiment to find what works for you. When I began CR, I dropped about 10 pounds without feeling hungry or deprived, but if I try to lose more, I run into just the problem you’re talking about. Other people have less difficulty, and certainly there are people who have more difficulty.
c) What’s your take on the paleo diet. I think it works great for glucose control. A dieted more balanced towards the vegetarian side would not lead to serious deficits in the body?. Any resource/link for sound vegetarian diet?.
>> Paleo diet has the theory all wrong, but in practice it’s not bad.
d) I find fascinating the Methathione theory. Have you read the research by Thomas Gettys
he has an article on the effect on a synthetic diet low on Methionine.
>> There’s no practical way to restrict methionine. Animal experiments use synthetic foods, as you say, which are both un-appealing and ultra-expensive.
>> – JJM