Background
The average adult human body contains more than 35 trillion cells.[155] Each cell is a little specialized unit dedicated to a specific task. But it cannot do its job alone, and it cannot survive without the others. To do their job and maintain our bodies, our cells are constantly communicating with each other. Much of this communication involves the brain. Thermoreceptor cells in the skin might report that it is becoming a little hot, stretch-receptor cells in the stomach are lining a signal that you’re full, pain receptors indicate that you stubbed your toe. Conversely, your brain might order your adrenal glands to produce cortisol (a stress hormone) during a tough day at the office or tell your saliva glands to ramp up production in response to the smell of fresh bread. All of this communication is done via nerves.
However, our cells also communicate over long distances via the bloodstream, and over short distances with the cells in their vicinity. For example, cortisol secreted in a stressful situation will diffuse through the blood and affect many different tissues. Similarly, many of the anti-aging interventions discussed in this report have a blood-borne aspect to them. During both fasting and exercise, many different factors are released into the blood, and these affect many different cells and cell types.[156]
Similarly, the immune system is engaged in intense communication to keep the body healthy. When an immune cell identifies an invader, it leaps into action and quickly alerts others. In its biochemical message to other immune cells, it includes information about the nature of the target and recruits other cells to help. Nearby blood vessels will become porous to admit more blood and immune cells to the tissue, for instance, and the cells lining the vessel will try to divert immune cells from the bloodstream to the site of danger. This process is called inflammation. Manifesting as redness, swelling, heat and pain, it may be uncomfortable, but it is very useful. The enhanced blood flow allows more immune cells and antimicrobial proteins to arrive and fight the intruder.
As we age, our immune system weakens, and one of the key organs of the immune system, the thymus, gradually shrinks.[157] The thymus is used for the maturation of important immune cells called T-cells, and its gradual shrinkage means that the number of these cells falls steeply with age.[158] This is one of the main reasons why our immune function is degraded with age. Few young people die of influenza, for instance, but with increasing age, the risk of death rises drastically.[159]
Paradoxically, even though the immune system weakens with age, it is accompanied by a rise in inflammation. In a phenomenon dubbed “inflammaging”, older people experience a lot of low-grade chronic inflammation spread out in their bodies.[160] The purpose of inflammation is to wipe out invading microbes; it is supposed to be a temporary condition. Having a constant low-level active inflammation is damaging. Inflammaging is known to play a role in the development of most cancers, heart disease, neurodegeneration, and other age-related conditions.[161]
It has been proposed that this inflammation can be dampened using anti-inflammatories such as aspirin. In male mice, supplementation with aspirin prolongs life.[162] In humans, doctors are discussing whether daily supplementation with aspirin is advisable, as it is known to decrease the risk of heart disease.[163][164]
Young blood
Non-immune intercellular communication also plays a role in aging. Scientists increasingly suspect that certain blood-borne factors (hormones and other signaling molecules) are key players. This idea stems from experiments with parabiosis in mice. Here two mice are surgically “tied together” so that they share a single circulatory system. When a young and an old mouse are paired like this, the old mice becomes rejuvenated (and the young mice grows frail).[165] Building on these results, scientists have found that the effect is due to the plasma of the blood (not the cells).[166] Plasma is the liquid component of the blood including dissolved proteins, electrolytes, hormones, and other molecules. In other words: It seems like that giving young blood to old mice makes them become rejuvenated.
Now the question is: Is the rejuvenating effect from adding the young blood (i.e., attributable to something in the young blood) or from diluting the old blood (i.e., attributable to something in the old blood?) The evidence is strongest for dilution of old blood. In a recent paper, scientists exchanged old blood plasma with saline and 5 percent albumin[167] The results of this procedure exceeded those of giving the old mice young blood as measured by the rejuvenating effects on muscle repair, liver adiposity, and hippocampal neurogenesis. For once, we have a human equivalent[168] - blood donors undergo a human version of this experiment. Each time the donors give blood, about 10 percent of their blood is removed. Afterwards, it takes the body a few weeks to slowly replace it. The comparison is interesting because we observe the same effect as in mice: Human blood donors tend to live longer, and more frequent donation is associated with a longer life. This could be due to hormesis, but could also be due to factors conducive to aging in the blood.
Challenges
The signaling environment of the body is highly complex. Different molecules have different effects based on the circumstances, and it is not easy to decipher what is potentially a pro-aging molecule.
In inflammaging, the issue of chronic inflammation could arise from infection with multiple viruses over a lifetime. For instance, it is known that the common cytomegalovirus often maintains a latent infection that exhausts the immune system.[169] In cases of infection, the inflammation has a purpose, and dampening it might be counterproductive (just like it is counterproductive to dampen the symptoms of fever during an acute infection). Others argue that much of inflammaging is really a sterile inflammation, somewhat similar to an autoimmune response. In that case, dampening the process as much as possible would be desirable.
In the business of blood transfusions from young donors, a startup company called Ambrosia Medical has caused controversy and damaged the credibility of the industry. The company leaped way ahead of the evidence and offered transfusions of young blood for US$8000 per transfusion.[170] In 2019, the Federal Drug Administration stepped in and prohibited the company from doing the procedure due to a lack of proof and the snake-oil like promises made to patients.[171] This has hurt the credibility of research in this field and pushed back progress. However, favorable scientific results should be able to turn it around.
Road to Success
Immunology is a very large and well-funded field, and we can expect progress here to have positive effects for life extension science as well. Interventions to regrow the thymus are especially promising, because this approach involves “resetting” the body to a younger state. This kind of intervention has the potential to facilitate major progress even before the process is understood in detail. When reset, the immune system will know what to do by itself.
In the field of young blood or plasma exchange, the next step is to identify the pro-aging factors in blood. Young blood turned out not to be rejuvenating; instead, it seems that old blood is pro-aging. The race is currently on to identify the specific proteins, hormones, and other molecules involved so that we can devise ways to block them. The Spanish pharmaceutical company Grifols has taken a slightly different approach. It produces albumin and has conducted a Phase 2 clinical trial of blood removal/replacement with its albumin product. This trial was aimed at combating Alzheimer’s disease, and the results were positive.[172] However, they still have to be confirmed in a Phase 3 trial.
Companies
Intervene Immune[173]
Website http://interveneimmune.com/
Email info@interveneimmune.com
Phone (833)3-466863
Industry Biotechnology
Headquarters Los Angeles, California
Type Privately Held
Founded 1998
Intervene Immune was founded by Greg Fahy, who has done extensive research on thymus regeneration, and Robert Brooke. The company is dedicated to reversing aging-associated involution of the thymus. By restoring the thymus, the company hopes to restore the immune system to a young state. As young people are much more resilient towards infections and have none of the immune dysfunction associated with age, Intervene Immune believes restoring the thymus will be life-extending for patients. The company has already performed a small clinical trial that showed positive results in humans.[174]
Alkahest[175]
Website http://www.alkahest.com
Industry Biotechnology
Company size 51-200 employees
Headquarters San Carlos, California
Type Privately Held
Founded 2014
Alkahest was founded by Tony Wyss-Coray and Karoly Nikolich. Wyss-Coray is responsible for much of the research on young blood and is the foremost expert in the field. Alkahest aims to translate the research on young blood into the clinic. The company researches the constituent elements of young blood to identify potential rejuvenating factors. It currently has several products in clinical trials, including AKST4290 against wet macular degeneration and Parkinson’s disease and AKST/GRF6019/6021 against Alzheimer’s disease.
Elevian[212]
Website https://www.elevian.com/
Industry Biotechnology
Company size 11-50 employees
Headquarters Boston, Massachusetts
Type Privately Held
Founded 2017
The administration of young blood has turned out to have many regenerative benefits in aged mice. The race is on to determine the mechanism behind this phenomenon. One of the best candidates is a molecule known as growth differentiation factor 11 (GDF11). When injected into aged mice, this treatment has many of the same regenerative benefits as young blood. Elevian is working to commercialize therapeutics based on this finding, which was made by the company founders and licensed from their labs at Harvard University.
Longevity Biotech[240]
Website https://www.longevitybiotech.com/
Industry Biotechnology
Company size 2-10 employees
Headquarters Philadelphia, PA
Type Privately Held
Funded 2010
The work of Longevity Biotech concentrates on a class of synthetic peptides called Hybridtides®, which the company anticipates can be used to design stable scaffolds for new drugs targeting neurological disorders and diabetes. One of these is LBT-3627, a novel neuroprotective agent that could be used to treat neurodegenerative disorders such as Parkinson’s disease. It has an immunomodulatory effect that restores immune function and has been paralleled by neuron survival in multiple pre-clinical Parkinson’s models. Its efficacy has been shown in mice.
References
[155] Bianconi, E. et al. 2013. An estimation of the number of cells in the human body. Annals of Human Biology 40(6):463-71.
[156] Horowitz, A.M. et al. 2020. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369(6500):167-73.
[157] Shanley, D.P. et al. 2009. An evolutionary perspective on the mechanisms of immunosenescence. Trends in Immunology 30(7):374-81.
[158] Gruver, A.L. et al. 2007. Immunosenescence of ageing. The Journal of Pathology, Special Issue: The Pathology of Ageing: Concepts and Mechanisms 211(2):144-56.
[159] Simonsen, L. et al. 1998. Pandemic versus epidemic influenza mortality: A pattern of changing age distribution. The Journal of Infectious Diseases 178(1):53-60.
[160] Franceschi, C. and J. Campisi 2014. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology, Series A, Biological sciences and medical sciences 69 Suppl 1:S4-S9.
[161] Ibid.
[162] Strong, R. et al. 2008. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7(5):641-50.
[163] Sanmuganathan, P.S. et al. 2001. Aspirin for primary prevention of coronary heart disease: Safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 85:265-71.
[164] The counterpoint is that this risk reduction might be outweighed by an increased risk of major bleeding.
[165] Conboy, I.M. 2005. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760-4.
[166] Villeda, S.A. et al. 2014. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 20:659-63.
[167] Mehdipour, M. et al. 2020. Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin. Aging 12(10):8790-819.
[168] Ullum, H. et al. 2015. Blood donation and blood donor mortality after adjustment for a healthy donor effect. Transfusion 55(10):2479-85.
[169] Powers, C. et al. 2008. “Cytomegalovirus Immune Evasion”, in: Shenk, T.E. and M.F. Stinski (eds.), Human Cytomegalovirus. Current Topics in Microbiology and Immunology (Heidelberg: Springer 2008), 333-59.
[170] Since the rejuvenating effect in mice is most likely due to dilution of old blood, not addition of young blood (see above), Ambrosia’s patients might have gotten a better result by keeping their money and donating blood instead.
[171] Hatmaker, T. ”FDA warning brings controversial young blood transfusion company to a halt”. TechCrunch.com, 19 February 2019. https://techcrunch.com/2019/02/19/fda-warning-blood-transfusions-ambrosia-medical/ (last accessed 6 August 2020).
[172] Loeffler, D.A. 2020. AMBAR, an encouraging Alzheimer's trial that raises questions. Frontiers in Neurology 11:459.
[173] http://interveneimmune.com/
[174] Fahy, G.M. et al. 2019. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18(6):e13028.
[175] https://www.alkahest.com/
[212] https://www.elevian.com/
[240] https://www.longevitybiotech.com/