Recent Considerations of Stem Cells and the Aging Process

Investigation of the contribution of stem cells to the process of degenerative aging is a flourishing field of research. As we age our stem cell populations gradually cease their activity, spending more time in periods of quiescence, and becoming more damaged by the wear and tear of continued metabolic activity. The principal role of stem cells is to provide a supply of new cells to keep tissues in working order, and diminished supply results in growing frailty and dysfunction. This is one of the causes of disease and death due to aging.

There are reasons for optimism, however. The stem cell research field is collectively one of the largest and most active scientific institutions in the world today. At present there are many possible avenues towards the development of therapies to slow or reverse those aspects of aging that are directly caused by growing stem cell dysfunction and quiescence. Further, since so many of the first generation regenerative therapies emerging from the study of stem cells are intended to treat age-related diseases, researchers in this field have a strong incentive to find and address all of the major age-related issues associated with stem cell biochemistry. They have to tackle these challenges in order to assure the effectiveness of their stem cell treatments. That said, this is of course only one of a number of fields that must all become this energetic and well funded if we are to see significant progress towards a comprehensive toolkit of rejuvenation therapies, many of which are far removed indeed from that level of support.

It is nonetheless encouraging to see progress on a near weekly basis reported in publications and the press. The latest issue of Cell Stem Cell features a number of open access papers on the role of stem cells in aging, illustrative of a range of current directions in research. I think you'll find them interesting:

Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline?

Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived, and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not. It is also unclear how evolutionary theories of aging that are currently accepted as at least plausible can be reconciled with the biological properties of somatic stem cells.

It is proposed here that somatic stem cell maintenance mechanisms lead to preferential accumulation, rather than disposal, of damaged stem cells. On the other hand stringent selection in the germline renders this lineage seemingly immortal. Furthermore, use of glycolysis for ATP production in somatic stem cells as opposed to mitochondrial respiration in the germline suggests that mitochondria play a critical role in stem cell maintenance and gamete selection. This hypothesis is consistent with prevailing evolutionary theories of aging, and with a critical role for mitochondria in aging.

Stem Cell Aging and Sex: Are We Missing Something?

A glance at the list of the human individuals currently living over the age of 110 - supercentenarians - reveals a surefire strategy for achieving such exceptional longevity: be female. Out of the 53 living supercentenarians, 51 are female. No other demographic factor comes remotely close to sex in predicting the likelihood of achieving such an advanced age. Sexual dimorphism with respect to longevity is a characteristic of most mammals and has been recorded in human populations since at least the mid-18th century. This dichotomous capacity for resilience has inspired wide-ranging hypotheses to explain the underlying mechanisms. It also raises questions regarding the sexual dimorphism of processes known to sustain tissue regeneration and function throughout life, including adult stem cell renewal.

Most adult stem cell populations undergo an age-related decline, leading to dysfunctional tissue homeostasis, which most likely participates in defining the ultimate lifespan of the organism. Interestingly, sex-specific regulation of stem cell populations has been demonstrated for several stem cell types, and it has long been appreciated that many canonical aging pathways exhibit sex specificity. However, despite the seeming interrelationship between sex, stem cell maintenance, and aging, few studies have sought to directly explore the interaction of these three variables. Here we discuss the sexual dimorphism of adult stem cell populations and how processes regulating the aging of stem cells may also be modified by sex.

Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency

Pluripotent stem cells (PSCs) are characterized by their ability to extensively self-renew and differentiate into all the cell types of the body. We propose PSCs cells as a novel model for studying human aging. Unlike traditional aging paradigms that focus on endpoints such as longevity or the restoration of regenerative capacity, PSCs allow us to monitor and manipulate molecular and cellular hallmarks of aging during both reprogramming and cell differentiation. Capturing the timing and sequence of the steps involved in cellular rejuvenation offers a unique opportunity for subsequent mechanistic studies.

The strong evidence for cellular rejuvenation during induced pluripotent stem cell (iPSC) induction indicates that many aspects of aging are reversible and may represent epigenetic rather than genetic barriers in biology. Therefore, a future is conceivable wherein it will be possible to reliably rejuvenate somatic cells without the need to move them back to pluripotency. In addition to studying rejuvenation, it will be equally important to identify novel induced aging strategies. The ability to direct both cell fate and age in iPSC-derived lineages will allow modeling of human disorders at unprecedented precision. Such studies could yield more relevant disease phenotypes and define novel classes of therapeutic compounds targeting age-related cell behaviors. The ability to program and reprogram cellular age on demand will present an important step forward on the road to decoding the mystery of aging.

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

The incidence of tissue dysfunction, diseases, and many types of cancer, including colorectal cancer and some types of leukemia, exponentially increases with age, and aging represents the single biggest risk factor for most cancers. However, the reasons for this aging-associated failure in tissue maintenance and the increase in cancer are poorly understood. Without a doubt, cancer is largely driven by genome dysfunction, frequently exemplified by specific genetic alterations that drive one or more specific cancer phenotypes. Overwhelming evidence indicates that the genesis and progression of cancer depend on accumulation of genetic alterations.

There is emerging evidence that aging induces changes in molecular pathways that accelerate the initiation and/or clonal dominance of mutations in stem and progenitor cells. The tight connection between aging-associated accumulation of stem and progenitor cell mutations with the failure of tissue maintenance and cancer suppression indicates a causal relationship between these factors. In addition to the cell-intrinsic mechanisms discussed here, there is increasing evidence that cell-extrinsic factors affect stem cell maintenance and possibly the selection of mutant stem and progenitor cells during aging. Likely, and potentially exciting, extrinsic candidates include aging-associated defects in the stem cell niches, alterations in the systemic/blood circulatory environment, changes in proliferative competition among stem and progenitor cells, inflammatory responses, and defects in immune surveillance of damaged cells. The delineation of this interplay of cellular and molecular mechanisms that contribute to the initiation and selection of stem and progenitor cell mutations in the context of aging will undoubtedly help the development of therapies aiming to improve early detection, prevention, and risk assessment of aging-associated diseases, organ dysfunction, and cancer.


That first paper seems to imply that mitochondrial mutations are very important in aging (at least from my brief skim read).

Personally I have a hunch that using TALENs to deplete the percentage of mutant mitochondria in cells may be the best way to deal with them (although I am just a layperson). This has the advantage of simply reducing the level of damage. The SENS Foundations approach of making the damage redundant by expressing the mitochondrial genes in the nucleus seems to be doing something more complicated. How do you ensure that the 13 mitochondrial genes expressed in the nucleus are expressed dymanically at the correct required level?

Posted by: Jim at June 4th, 2015 7:40 PM

"How do you ensure that the 13 mitochondrial genes expressed in the nucleus are expressed dynamically at the correct required level?"

That may not be possible, as Nick Lane argues rather convincingly in his latest book "The Vital Question." Lane (channeling Wallace) says that those 13 proteins are needed in the mitochondria to provide prompt local control of the production of ATP; that's why they never moved.

Lane's book is spectacular, by the way...

Posted by: Gary at June 4th, 2015 10:35 PM

Hi Jim,

This approach won't work for the kind of mitocnondrial mutation that's relevant to aging. Purging out pathological mitochondrial genomes works when many cells have a mix of normal mito genomes and others that are actively toxic to the cell, which is what's going on in a lot of mitochondriopathies but is evidently a very rare situation in aging cells (and where it happens, it's confined to the cell in which it originates, so it has little effect on the overall function of the tissue in which it resides, and doesn't worsen with age).

The kind of mitochondrial mutation that — while rare — actually does accumulate in aging tissues in a meaningful sense is large deletions, and when those occur they very rapidly take over the entire cell. Thus, you have no real opportunity to "tip the scales," and eliminating the mutant genomes leaves you with a cell with no mitochondria at all, which is functionally the same and (per Dr. de Grey's theory) still causes the cell to adapt the same abnormal metabolic state in order to carry out minimal function and in the process spreads oxidative stress to the rest of the body. See Dr. de Grey’s reasonably accessible thesis adaptation, or chapter 5 of Ending Aging. To solve this problem, you have to actively restore the proteins of the electron transport chain, one way or another.

Posted by: Michael at June 5th, 2015 5:56 PM

It might be pie in the sky right now, but couldn't you introduce a fresh mitochondria into each cell along with the endonuclease? DNA nanocages might fit the bill for delivering this kind of therapy.

Posted by: Jim at June 5th, 2015 9:49 PM

There is already technology to digitally synthesise dna slightly longer than mtDNA. But I believe our cells are already capable to kill defect mitochondrias and they are mutating fast enough to create "good" ones spontally. For some reason this selection declines with age as do other repair mechanisms.

Posted by: Martin S. at June 7th, 2015 2:16 AM

Jim: it's hard enough to get viral vectors for gene therapy to do somatic gene therapy; I shudder to contemplate simultaneously introducing a new founder mitochondrial population AND a suitable restriction endonuclease in every single cell (or, more reasonable, the great majority of postmitotic cells), and then having to do that over and over again since new mutations are generated ongoingly. The brain alone contains 100 billion neurons, plus other cell types ...

By the way, I see that I forgot to address the "How do you ensure that the 13 mitochondrial genes expressed in the nucleus are expressed dynamically at the correct required level?" question in your earlier query. The answer is that this is very unlikely to pose a problem. First, we don't have to get a maximal level of allotopically-expressed proteins up and running in the mutation-bearing mitochondria — just enough to keep OXPHOS going at the low level required to avoid chronic exclusive glycolysis (see Dr. de Grey's thesis or Chapter 5 of Ending Aging).

Second, remember that the majority of the electron transport chain machinery is already encoded in the nucleus; we can either actively make use of the same machinery for regulation of expression (since there are nuclear-encoded electron transport proteins in the same Complex as (and thus requiring fixed stoichiometry with) proteins encoded by genes that are currently located in the mitochondria of which we'll make copies in the nucleus), or rely on existing mechanisms whereby mt control the level or activity of nu-coded proteins (regulating their importation rate or modulating enzyme activity allosterically, eg:

Bender E, Kadenbach B. The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett. 2000 Jan 21;466(1):130-4. PMID: 10648827 [PubMed - indexed for MEDLINE]

Thus, for example (and apologies if I lose some readers here), cytochrome b of Complex III is mt-coded, but the other dozen subunits are nu-encoded in 1:1 ratio. The Complex can't function if the proteins' stoichiometry isn't maintained, so expressions of all subunits has to be coordinated. Cells already successfully synchronize Rieske protein and other subunits in lockstep with cytochrome b, and do so in response to actual requirements rather than constitutively, despite the fact that the transcription and translation of the various subunits, and the machinery that performs it, are distinct.

And if worse comes to worst and it turns out to be necessary for us to actively control the expression patterns to match requirements really well, there's a fairly straightforward solution: we take the regulatory sequence of (for example) Rieske protein, and we preface it to cyt b, and voilà — instant lockstep regulation of expression. And so on with any other allotopically-expressed proteins that prove problematic in similar ways. Some of the main arguments about the regulation of allotopically-expressed mitochondrial proteins were discussed a while ago on Longecity, and you might want to have a look at this paper:

de Grey AD. Forces maintaining organellar genomes: is any as strong as genetic code disparity or hydrophobicity? Bioessays. 2005 Apr;27(4):436-46. PMID: 15770678

... which inter alia discusses the idea (favored by Nick Lane a decade or two ago, as Gary mentions) of a strong within-the-mito REDOX regulation of Complex protein expresion, which some have argued exists and would prima facie be a problem if it occurs.

Martin: Yes, the cell already knows how to destroy a certain kind of dysfunctional mitochondria; unfortunately, this is the very mechanism that Dr. de Grey argued in his thesis is ultimately responsible for the takeover of the cell by the really problematic mitochondrial population as regards aging (those bearing large deletions in their mtDNA) — a postulate/prediction that has recently been experimentally validated by starting with work by John Youle (he did a good presentation at the Sixth SENS Conference, for which unfortunately we still haven't uploaded a video, but see "Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells" and "Parkin is recruited selectively to impaired mitochondria and promotes their autophagy"), which goes to your correct perception/intuition, but then balance this with below) and pairing it with this recent finding from Judd Aiken's powerhouse team (pun intended): "Mitochondrial Biogenesis Drives a Vicious Cycle of Metabolic Insufficiency and Mitochondrial DNA Deletion Mutation Accumulation in Aged Rat Skeletal Muscle Fibers."

Posted by: Michael at June 7th, 2015 12:27 PM

Thanks for the replies Michael, I'm going to stop asking questions as I'm getting the same feeling I used to as an annoying undergrad. I should probably just go off and read Primrose.

Interesting to know that trasfecting the relevant cells will probably be orders of magnitude easier than transferring full mitochondria to them.

One last question... why not just use the 'wonder-crispr' on Killifish embryos to whack the relevant genes with the RNA tags that allow them to be translated near the mitochondrial surface, then see if there are any lifespan/healthspan effects?

Posted by: Jim at June 10th, 2015 6:59 PM

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