The Alternate View

A Mitochondrial Jumpstart for Age Reversal
by John G. Cramer

Mitochondria are the powerhouses of living human cells. They are tiny bacteria-like organelles that reside within a cell and provide it with energy, busily converting food-derived molecules into ATP (adenosine triphosphate, C10H16N5O13P3), the fuel that cells actually use for all of their energy needs. Humans go through around fifty kilograms of ATP per day, and each mitochondrion in a human cell produces about 108 ATP molecules per second.

The number of mitochondria in a human cell depends on its cell type and its energy needs. For example, small-intestine villi have around 21 mitochondria, skin cells have a few hundred, liver cells have 1,000—2,000, and heart muscle cells, with high energy needs, have around 5,000. The cells of hair follicles also contain many mitochondria, and age-related hair loss has been attributed to mitochondrial dysfunction. In contrast, blood platelets have only about five to eight mitochondria, and mature red blood cells have no mitochondria at all.

Each human mitochondrion contain two to ten copies of its personal DNA genome, in the form of a double-stranded DNA ring made of about 16,569 base pairs that encode 37 genes, 28 on the ring’s heavier DNA strand and nine on the lighter strand. The remarkable similarity of mitochondrial DNA rings and those in certain bacteria has led to the conjecture that about 1.8 billion years ago, early in the evolution of complex life forms, some developing single-cell organism, by a stroke of good luck, happened to capture a free-living proto-mitochondrion bacterium and integrated it into its functioning, giving that cell a large energy-boost advantage over its many competitors. That single-cell organism, through a very long and twisty evolutionary chain, is our ancestor.

The build-a-protein RNA coding used by the mitochondrial DNA (mDNA) of a cell is slightly different from the coding of the cell’s nuclear DNA, because the mitochondrion uses its own ribosomes (protein assemblers), and those respond to slightly different RNA coding from the ribosomes used by nuclear DNA. Similarly, the genetic correction mechanisms for repairing errors and breaks in mitochondrial DNA are different and less effective than those for nuclear DNA.

As a consequence, damage accumulates in mitochondrial DNA faster, leading to more rapid degradation-with-age of mitochondrial DNA. This effect is partially compensated by the presence of multiple copies of the mDNA ring within each mitochondrion and the presence of multiple mitochondria in each cell. Ultimately, however, a sizable fraction of a mitochondrion’s mDNA rings become corrupted, and the organelle will fail.

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As humans age, there are many negative changes that ultimately lead to decline and death: (1) a cell’s epigenetic programming, the pattern of methyl radicals attached to CpG sites on the underlying DNA structure, devolves from a “young” profile to an “old” profile, telling the cell that it is old by selecting and changing which proteins it is currently expressing; (2) damaged cells become senescent, stop cell division, cease to perform their intended cellular functions, and instead begin producing harmful SASP (Senescence-Associated Secretory Phenotype) secretions that can induce senescence in their cell-neighbors; (3) the telomeres at the ends of chromosomes become too short and block cell division; (4) a cell’s nuclear DNA accumulates unrepaired mutational changes and double breaks, leading to cellular malfunction, and, (5) perhaps most important, a cell’s mitochondria fail and shut off the cell’s vital energy supply. Modern anti-aging biotechnology has focused on these problems, and many research groups and commercial firms are in the process of developing interventions to correct each of them. In previous Alternate View columns (AV 88, AV 194, AV 202, and AV 211) I described the development of interventions aimed at fixing telomeres, senescent cells, and epigenetic programming.

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The standard lab mouse is widely used in age-related experiments. They have an average lifetime of about 26–30 months and a maximum lifespan of about three years. The age-related effect that sets the hard limit on the maximum lifespan in mice is not known. However, that limit for short-lived mice (~3 years) probably has a different root cause from that for long-lived humans (~120 years). Nevertheless, the researchers investigating interventions that may combat the effects of aging are very interested in the impact of their interventions on the lifetime, health-span, and maximum lifespan of their lab mice.

There is now a body of age-related animal experimentation in which these interventions have been applied to aging mice to fix various aging problems. In particular, researchers have genetically modified strains of test mice to: (1) express on chemical command a group of Yamanaka factors for epigenetic reprogramming, (2) on chemical command trigger apoptosis (pre-programmed cell death) in senescent cells expressing protein p16, and (3) on command express telomerase to lengthen telomeres. In each of these cases, the test subjects have shown remarkable improvements in appearance, performance, and health, but none of the interventions has significantly extended the maximum lifespan of the test animals. Similar tests involving mitochondria repair (4) are in progress, but the work is too new and the mice too young to provide any data on mouse lifespan. (We note that the Methuselah Foundation’s MPrize, a 2003 challenge to extend a mouse lifespan beyond three years, was recently won by a researcher who extended the lifetime of a test mouse to about five years using an intervention that combined insulin, glucose, and genetically modified growth hormone.)

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Mitrix Bio Inc. of Pleasanton, CA is a biotech startup that has taken on the problem of mitochondrial decline and its correction. For a start, they have invented a new procedure for testing the condition of mitochondria. In evaluating the effectiveness of any anti-aging intervention, it is important to have measurements that indicate whether any improvement is actually been achieved. Using the new long-sequence PCR technology, Mitrix has developed a new technique for quantitatively characterizing the degree of DNA damage present in mitochondria from a subject’s urine sample. In one dramatic example, they show damage plots for the same mitochondrial DNA pattern taken from three family-related subjects 32, 62, and 93 years old. These show mDNA damage scores of 7%, 11%, and 25%, respectively. There are indications that a subject is not likely to survive if the mitochondrial damage level reaches 25% or more, because energy production by the mitochondria becomes too inefficient to sustain life. In other words, there is now evidence that mitochondrial damage, which will severely limit the energy available to otherwise healthy cells, may be a principal contributor to the maladies of old age.

So, is there an intervention that can correct this problem? The intervention being developed by Mitrix has the following steps: (1) obtain a sample of pluripotent stem cells from the subject or from a maternal-chain relative, possibly by liposuction of body fat; (2) amplify the population of stem cells by perhaps x10,000 by repeated cell division in a bioreactor; (3) extract and purify the mitochondria from these stem cells and arrange for the extracted mitochondria to be encased in “mitlets”, i.e., protective vesicles that can deliver the mitochondria to cells without triggering the immune system; and (4) slowly infuse the subject with these mitlets, into the bloodstream or at particular target sites (eyes, joints, muscles, etc.) where the mitochondria will enrich the mitochondrial count of the target cells and reinvigorate them. A form of this intervention is now being performed on lab mice, with very encouraging preliminary results.

The cell-replication part of this procedure is expensive and time consuming, but for now it is the only one that is available and proven effective. Far on the technical horizon are faster and cheaper alternatives: (1) using some form of long-chain PCR to amplify only undamaged mDNA rings, or (2) genetically modifying some fast-growing bio-organism, e. g., yeast cells, to internally synthesize either the entire mitochondrion or its mDNA ring. Either of these developments could potentially reduce the cost of mitochondrial replacement by orders of magnitude and reduce the amplification time to a few days.

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One question prompted by the Mitrix intervention is whether the stem-cell amplification process, if using cells taken from an elderly subject, will simply reproduce the existing mDNA damage that the subject has accumulated. Fortunately, there is evidence that, with the proper chemistry and biology, the process of stem cell division can be modified to produce undamaged mDNA, so that repeated stem cell division tends to purify the mDNA content. Thus, the process described above should produce mitlets containing mitochondria with relatively undamaged mDNA.

Another common concern is that mitochondria in the bloodstream won’t be easily absorbed into cells. This is based on the orthodox view of mitochondria as stable organelles residing tamely within cells. However, mitochondria in the bloodstream have been found to be extraordinarily mobile and can easily pass through cells membranes and, when encapsulated in extracellular vesicles, move around the body in large numbers. For example, platelets in the blood (100 billion created daily) are effective for about ten days and then, before being recycled, eject their five mitochondria encased in extracellular vesicles coded with special receptors. These are absorbed readily by nearby white blood cells, platelets, and other immune cells. One can view the mitochondria in extracellular vesicles as “interchangeable battery packs” that boost the immune system and that cells recycle and loan to each other to conserve all-important energy for survival of the organism. A similar mechanism in the brain, recently discovered, transfers healthy mitochondria from astrocytes to neurons, then transfers burned out mitochondria from the neurons back to the astrocytes for refurbishment. Thus, there seems to be a huge, highly optimized “mitochondrial distribution system” at work in the body. This is perhaps the most under-researched and under-utilized concept in modern biology. New mitochondrial-transplantation startups like Mitrix are racing to develop mitochondrial interventions and to make them available to the aging population.

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So what happens next with Mitrix? The plan is soon to conduct an offshore Phase 1 Safety Trial of the mitochondrial replacement intervention performed on a selected group of human subjects. My birthday is in October, and by the time you read this, I will be ninety years old and still in good health. I have volunteered to be in the first cohort of subjects who will participate in this Mitrix Mitochondrial Safety Trial, to be held in a year or so.

Watch this AV Column for further developments. If and when, I’ll let you know how this mitochondrial jumpstart works out.

 

References:

10. Adlimoghaddam, T. Benson, & B. C. Albensi, “Mitochondrial Transfusion Improves Mitochondrial Function Through Up-regulation of Mitochondrial Complex II Protein Subunit SDHB in the Hippocampus of Aged Mice,” Molecular Neurobiology 59(10), 6009—6017 (2022); https://link.springer.com/article/10.1007/s12035-022-02937-w.

Martin Pelletier. Yann Breton1, Isabelle Allaeys, Yann Becker, Tom Benson, Eric Boilard, “Platelet extracellular vesicles and their mitochondria content improve the mitochondrial bioenergetics of cellular immune recipients,” Transfusion 2023, 1-14 (2023).

Nicholas Borcherding and Jonathan R. Brestoff, “The power and potential of mitochondria transfer,” Nature 623, 283-291 (2023).

 

John’s new third hard SF novel, Fermi’s Question, and its prequel, his second hard SF novel Einstein’s Bridge, are available as eBooks from Baen Books at https://www.baen.com/einstein-s-bridge.html. His first hard SF novel Twistor is available online at: https://www.amazon.com/Twistor-John-Cramer/dp/048680450X. John’s 2016 nonfiction book The Quantum Handshake—Entanglement, Nonlocality, and Transactions, (Springer, January 2016) is available online as a hardcover or eBook at: https://www.amazon.com/dp/3319246402.

Copyright © 2024 John G. Cramer