Changes in gene expression underlie aging and age-related diseases. There is all-but-universal (and equally unwarranted) assumption that both aging and age-related diseases are genetic. We see articles on “aging genes” and “genes that cause Alzheimer’s disease” (or genes that cause heart disease, osteoarthritis, etc.). The reality is that both aging and age-related diseases are not […]
Aging and Disease: 2.3 – Cell senescence, Changes in Gene Expression
- beta amyloid
- Curing Alzheimer's
- Human Trials
Changes in gene expression underlie aging and age-related diseases. There is all-but-universal (and equally unwarranted) assumption that both aging and age-related diseases are genetic. We see articles on “aging genes” and “genes that cause Alzheimer’s disease” (or genes that cause heart disease, osteoarthritis, etc.). The reality is that both aging and age-related diseases are not genetic, they are epigenetic.
To get at the difference, albeit in a slightly different context, consider the difference between a skin cell and a nerve cell. These cells have the same genes, but very different gene expression. The difference between a skin cell and a nerve cell is not genetic, but epigenetic. Same genes, different gene expression.
The same is true of aging cells. The difference between a typical young cell and a typical old cell is not genes, but gene expression. The two cells – for example, a young skin cell and an old skin cell – have the same genes, but very different patterns of gene expression. What makes a cell “old” is not gene damage or altered genes, but alterations in the way those genes are expressed. To use the analogy of a symphony orchestra, both young cells and old cells have the same orchestral instruments (violins, oboes, etc.), but they’re playing slightly different scores (Mozart instead of Bach, as it were). Old cells aren’t old because their “instruments” (the genes) are “out of tune”, but they are old because they play a different tune.
This alteration in gene expression underlies all age-related diseases. The reason we have heart disease, dementia, osteoarthritis, osteoporosis, or other hallmarks of aging (including things like wrinkles, that aren’t actually diseases at all), is because certain cells have an altered pattern of gene expression. Same genes, different gene expression.
A growing number of papers have pin-pointed specific changes in gene expression that are present in old cells and old tissues, but they focus narrowly on such changes as “the” important change, then explore how they might address that single, specific change. They see a single “tree” (of a change of expression in single gene) but lack the ability to see the larger “forest” (encompassing the gamut of changes in expression in hundreds of genes). Too often, they view each change as a “cause” of aging, not realizing that each single change is an effect, caused in turn by a more fundamental process: the shortening of the telomere. In fact, there are literally hundreds (perhaps thousands) of such changes, all of which are not, by themselves, causes of disease or aging, but are the results of changes in telomere length. Aging – and age-related diseases – are not the result of one gene, nor the result of the change of expression in one gene, but rather the result of wholesale and subtle changes of expression in many genes, acting in concert. To harp back to the orchestra: the problem is the orchestral score, not the orchestral instrument.
Nor are do such epigenetic changes stop there. As the telomere influences the expression of a few local genes, these in turn influence the expression of more distant genes, which in turn influence genes on other chromosomes. Moreover, there are interactional effects between such genes: gene a1 may affect three other genes, but such “downstream” genes may well be influenced by other genes as well.
Views of aging (or disease) that focus only on one particular gene or gene product (any of the various “x’s” at the bottom of figure 2.3a) miss the complexity of the process. As examples of this, we see human trials that, in the case of Alzheimer’s disease for example, focus narrowly upon particular gene products, such as beta amyloid (or genes, such as APOE4), then express confusion and surprise when carefully thought out interventions (aimed only at beta amyloid) fail to have any impact on the progressive course of the disease. These trials my employ an effective intervention for one particular gene or gene product, but they ignore the expression of other genes and ignore the complex interactions of multiple genes, all of which are undergoing changes in gene expression as the cells age.
Such human trials remove one tree and then wonder why the forest is still there.
Moreover, as we will see, even when you restrict your focus to a particular gene, the problem is not the product itself, but the rate at which it turns over. To stretch our tree and forest analogy, even if you restrict your view to one particular tree, you find that it keeps regrowing. The question isn’t “can you cut the tree”, but “how often you need to recut the tree?” Beta amyloid, for example, is continually being turned over. Simply lowering the amount of amyloid (“cutting the tree”) won’t work – as many human trials aimed at amyloid have shown – because amyloid is a dynamic pool (a “tree that keeps regrowing”).
The problem comes back to the telomere. Not only isn’t it enough to focus on a single gene, a single protein, or a molecule, but even if you use a broader view and look at all the changes in gene expression – modulated by changes in telomere length – you must realize that every single gene, protein, or molecule is dynamic. Alzheimer’s, for example, is not JUST a matter of beta amyloid, but a matter of dynamic turnover in the amyloid pool. To account for the broad changes, you need to account for ALL the gene changes and account for the turnover rates as gene expression changes.
Trying to treat disease is much like trying to treat hundreds of dynamic processes all at once. You can try aiming at all the processes with hundreds of drugs, you can even try to find a drug that will increase the turnover rates of all these hundreds of processes with hundreds of drugs, one-by-one and with interactive side effects. The actual processes that encompass these age-related changes in gene expression are stunningly complex, encompassing DNA methylation, histone tails and other histone modifications, nucleosome positioning, micro RNA’s (miRNA’s), repressor proteins, i-motif DNA “knots”, and probably dozens of other “tools” of our epigenetic landscape, but the details of these processes lie well beyond our current discussion.
The upshot is plain, however. We could focus one-by-one on each of thousands of individual genes, we could focus one-by-one on each of dozens of different regulatory processes, and for each of these thousand genes or dozen processes attempt to develop (one-by-one!) effective interventions, then hope to combine all of these interventions (while hoping there are not interactive side effects) and use them to treat age-related disease by giving thousands of small molecule drugs.
Or, we can simply reset gene expression by addressing the change in telomere lengths.
Next time: 2.4 Cell Senescence, Changes in Molecular Turnover
It is the case that relative telomere length declines with age in key stem cell compartments, in mice. This decline in relative telomere length incurs the progressive deterioration of stem cell homeostasis
( homeostatsis is the maintenance of the cell in satisfying working order). This gradual loss of stem cell homeostasis may drive gradual loss of the organism’s homeostasis with age.
(for refence: The longest telomeres: a general signature of adult stem cell compartments. authors: Ignacio Flores, Andres Canela, Elsa Vera,Agueda Tejera, George Cotsarelis and María A. Blasco ; 2008, Genes & Development)
Another informative entry, thank you. Will the recent accurate imaging of the telomerase enzyme have any impact on your work?
Accurate imaging of telomerase will have little practical implication for our work. The analogy might be to consider the impact of accurately imaging the polio virus (a scientifically desirable goal) versus the production and availability of an effective polio vaccine (a clinically desirable goal). We applaud the former, but we value in the latter.
Hello again Dr. Fossel!
Thank you very much for sharing these wonderful insights on telomeres, telomerase and its role in the aging process. I’d very much appreciate it if you can comment on your expectations for the first trial to combat Alzheimer’s disease by restoring telomeres to their original length. More specifically, is your therapy aimed at “only” reversing this terrible disease or, do you expect that the therapy will likely have other, unexpected but very much welcomed, side affects and if so, what do you think, on a broad sense, those benefits might be
Again, thank you very much!
Our intent is to aim initially and specifically at Alzheimer’s, largely for strategic reasons: AD is fatal and has no currently effective therapy. However, our intent is (after the AD trials) to broaden our scope to both other age-related dementias (e.g., Parkinson’s, F-T, vascular, etc.) and to other age-related diseases generally (e.g., age-related vascular disease, osteoarthritis, etc.). Note that our stated intent is not to “extend the human lifespan” (although we regard this as both feasible and reasonable), but to effectively treat (prevent and reverse) age-related diseases. Put differently, we are aiming at human pain, suffering, fear, and the tragedy involved in human disease. Extending the lifespan is incidental to our goal.