How Young Blood Differs from Old

“Young Blood May Contain Chemical Factors Which Can Prevent or Reduce Some Effects of Aging” read the science headlines after Saul Villeda published his article last year about rejuvenating mice with successive transfusions from young animals. Learning what blood factors we are missing as we get older is a promising new frontier in anti-aging medicine, but more powerful yet is the realization that there are other blood factors that increase as we get older, with destructive consequences for our nerves, our stem cells, and the integrity of our metabolisms. (This entry continues a thread from last March, based on the ideas of Harold Katcher.)

Background

Blood is best known for for blood cells.  Red corpuscles carry oxygen so every cell in the body can breathe.  White corpuscles are legions of the immune system, ready to detect invading organisms or errant internal cells, to search and destroy.  On a smaller scale, our blood also carries hormones, large specialized protein molecules that constitute a signaling system for regulating the metabolism from moment to moment, making us hypervigilant or putting us to sleep, for example.  Smaller yet are signaling molecules that are much simpler than proteins, that are broadcast by various organs but especially parts of the brain, and that constitute the marching orders, directing activities at the cellular level.

We know now that some of what these small chemical messengers do is to orchestrate a process of self-destruction later in life, a function we refer to as “aging”. We don’t yet know how much of the aging process is triggered by these signals, or how reversible the process might be if “young signals” replace the “old signals”, and we don’t know how many separate signal molecules there might be, or which are the ones that are most important. It is vitally important that we learn these things. It is our next step.

Parabiosis experiments

Saul Villeda (formerly at Stanford, now UC San Francisco) is studying the blood signals that trigger and regulate the aging process.

Villeda’s research involved connecting the circulatory systems of two mice by a technique known as heterochronic parabiosis, which is typically used to study immune systems. After the blood of the old mice and young mice had mixed, Villeda found that the older mice showed distinct signs of a slowdown or even a small reversal in the aging process. The brains showed an increase in stem cells, and the connections between neurons had increased by 20%.

In [a not-yet published] study, Villeda and his team also tested the mice’s behavior.  Villeda injected small amounts of blood plasma, the liquid portion of blood, from two-month-old mice into 18-month-old mice eight times over the course of a month. The amount of plasma used was approximately 5% of a mouse’s total blood volume. Villeda then had the mice solve a water maze, an activity in which mice have to remember the location of a platform. Untreated older mice made mistakes as they attempted to solve the maze, such as swimming down blind alleys. Mice who had received the young plasma, however, often found the platform on their first try and performed similarly to mice four to six months of age.

Villeda…believes that treatments based on factors found in youthful blood may eventually be able to help middle-aged people prevent some of the worst effects of age-related deterioration, possibly even Alzheimer’s disease. “Do I think that giving young blood could have an effect on a human? I’m thinking more and more that it might,” he said. “I did not, for sure, three years ago.”
[from The Guardian]

In his parabiosis experiments, Villeda surgically joined the circulatory systems of young and old mice.  One of the effects he discovered was new nerve growth in the old mice receiving young blood.  He went on to ask what substances in the blood triggered this benefit, and homed in on a blood factor called CCL11, a chemokine, a kind of protein signal molecule involved in development and regulation of growth. CCL11 is not a promoter of growth, however – just the opposite.  It is one of those signals that we have too much of as we age, and it inhibits nerve growth. Villeda injected young mice with CCL11 and found that their nerve growth was slowed.  More to the purpose of anti-aging medicine, he was able to stimulate nerve growth in older mice by injecting them with antibodies to CCL11.

Biochemical dramas have few unequivocal “bad guys”, and much depends on context.  Mice without the receptor for CCL11 (called CCR3) have developmental deficiencies.  So the best guess so far is that we have too much CCL11 as we age, but that we wouldn’t want to eliminate it altogether.  (This article by Richard Ransohoff in Nature, summarizes Villeda’s work and places it in context.)

Parabiosis experiments are more than a century old, but have received new attention in the study of aging beginning with Irina and Michael Conboy about ten years ago. Their research continues with their collaborators at Harvard and University of Cambridge.  Parabiosis experiments are important for demonstrating the principle that young blood contains something that rejuvenates, and that old blood contains something that inhibits renewal.  But they are hardly a practical solution for humans.  In this sense, the work of Villeda points to a new path, in which these blood factors are isolated and their pathways understood, so that a cocktail can be prepared which might offer the advantages of “young blood”.

The Big Question: Which chemical components of blood are important for aging?

I’ve been compiling two lists:  Blood factors that we have too little of as we get older, and blood factors that we have too much of.  Over the next couple of weeks, I will research these one by one and report in this column what I find.

In the meantime, if you, dear reader, are aware of other blood factors that I should be considering, please help me to augment these lists.

Blood factors that we have too little of as we get older

• melatonin, from pineal gland, controls daily cycle of sleep and waking
• DHEA = dehydroepiandrosterone is a precursor of sex hormones and steroids
• ubiquinone = CoQ10 is an anti-oxidant and electron transporter, used in mitochondria for energy production
• thyroxine, produced in the thyroid, regulates many other hormones, stimulates activity
• HSP70, heat shock protein, protects against muscle loss with age
• progesterone, involved in menstruation, sleep cycle, mood; downregulates growth, increases insulin sensitivity
• (HGH = human growth hormone)
• (testosterone) primary male sex hormone
• (estrogen) several primary female sex hormones

The last three in this list are sex and growth hormones.  They are in parentheses because, even though their prevalence declines with age, I believe that they are actually counter-productive, and may hasten aging.

Blood factors that we have too much of as we get older

• Wnt, a growth promoter associated with cancer
• NFkB, a cytokine which triggers inflammation
• LH (luteinizing hormone) & FSH (follicle-stimulating hormone), associated with ovulation in women and sperm production in men.  Increase late in life for both men and women.
• Estradiol, a female sex hormone
• CCL11 (a growth-inhibiting chemokine, see Villeda’s work above)