Cellular Senescence Presented as the Causal Nexus of Aging
In the open access paper I'll point out today, a group of researchers who focus on the phenomenon of cellular senescence present their argument for cellular senescence to be the central process in aging. It has to be said that I'm bullish on the clearance of senescent cells as a strong first step towards a toolkit of therapies for human rejuvenation, especially now that startup companies are working on it, but it is important to recognize that the accumulation of senescent cells is just one of a number of fairly independent mechanisms that contribute to aging. Yes, the damage caused by these mechanisms interacts, but the sources of that damage are very different. Removing one only helps to the degree that you have removed one. The others will still get you, because all of them are associated with at least one fatal age-related disease. You can take a look at the introduction to the SENS vision for rejuvenation therapies for a list of the forms of cell and tissue damage that contribute to degenerative aging.
I think we've all heard the fable of the blind men and the elephant deployed in connection with aging research. The life sciences are overwhelmingly populated by specialists, as biochemistry and medicine are both so very complex that productive work requires a narrow focus. Investigating one tiny area of cellular biochemistry can be the focus of an entire career. Even when you can see what you are doing, when poised two centimeters from an elephant's face, the creature is essentially a trunk - and maybe some other stuff back there that obviously can't be as important as the giant trunk occupying your field of vision. The elephant of aging is surrounded by hundreds of researchers, each of whom is focused intently upon a small piece of the whole. There are far too few generalists working to link parts of the field and make otherwise disconnected researchers aware that they are looking at the same biochemistry through different lenses.
In any case, this is a very long-winded way of saying that one should be cautious about any analysis that places one particular mechanism at the center of aging. It isn't at all clear to me that aging has a center, and the research community is still unable to say with confidence that any one of the the forms of cell and tissue damage listed in the SENS view of aging is more or less important than the others. The way we will find out which of the forms of age-related damage is the most important is by firstly developing the means to repair that damage and then secondly watching the results of repair therapies in animal models - which is exactly what is happening at the moment for senescent cell clearance. The try it and see approach will get to answers a lot faster than any of the much more analytical alternatives.
Cellular Senescence as the Causal Nexus of Aging
In 1881 the evolutionary biologist August Weismann proposed that "Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting but finite." How did he arrive at such a bold conclusion? Weismann observed that during evolution, simple multicellular organisms such as Pandorina Morum, which were immortal, gradually evolved into mortal organisms such as Volvox Minor. The absolutely crucial difference between these two organisms is that while Pandorina's cells were undifferentiated and divided without limit, Volvox's cells had differentiated into two very different types: the Somatic (body) cells, and the Germ (reproductive) cells. Thus, while the germ line has retained the capacity for infinite renewal, the body cells have not; they age and expire. While Weismann's hypotheses were remarkably prescient, at that time neither DNA nor cultured cells were sufficiently understood to allow his theory to be adequately tested. In fact, it was not until nearly one hundred years later, following the development of sophisticated animal cell culture protocols, that he was proven correct: it was shown that somatic cells grown in culture have limited growth potential. After approximately forty passages, human cells stop proliferating and undergo cellular senescence.Besides Weismann's evolutionary theory, many additional theories have been proposed to explain the complexity of aging. These include the antagonistic pleiotropy theory, the free radical theory, age-associated shortening of telomeres, development of insulin resistance, decreased immune function, the mitochondrial theory, as well as deregulation of the circadian clock. While these theories indicate functional diversity in the etiology of aging, it must be stressed that each one relies on the concept of internal alterations in individual cells, and does not explain how the microscopic cellular damage manifests as macroscopic aging and tissue breakdown in the organism (with a few exceptions, such as changes in hormone function and declines in immune function). Theories of mutation accumulation and antagonistic pleiotropy address the genetic causes of aging, and environmental stress or lack of it contributes to modulation of the epigenome as well as physiological alterations in different tissues of the whole organism, but each theory revolves around the functional competence of different components of cells and again does not explain how this manifests as macroscopic organismal aging. Experimental evidence unifying the interactions of some components has started to emerge, but we propose that all of the changes described by diverse theories ultimately converge on the cellular senescence theory.
Since aging is a progressive condition that steadily advances from invisible to visible and localized to ubiquitous, the central question as to the direct cause of the entire process is key. The answer has been elusive due to its complex nature. Our model proposes that the process of aging results from a sequential passage through three distinct phases and can be described by the following blueprint: (1) molecular damage which results in (2) cessation of proliferation leading to cellular senescence followed by (3) body-wide aging of the organism. The first step occurs when localized, microscopic damage accumulates to a point where the burden to repair overwhelms the system. Despite the tissue source or broad input of molecular damage, crossing of this threshold results in the second phase, the crux of the entire process - arrest of cellular proliferation, acquisition of the senescence-associated secretory phenotype (SASP), and imminent cellular senescence. Once this occurs, the third phase of aging begins. This final phase is marked by tissue dysfunction and breakdown that results in the visible signs of comprehensive organismal aging.
The incremental advance proposed by our model is that while there are many undisputed factors that trigger the onset of cellular senescence and result in cessation of proliferation and SASP, the first phase in the model (cumulative molecular damage) is a precursor, rather than a final cause of aging. The complexity normally imposed by countless variables (i.e., age of onset, site of damage, affected cell type, mechanism of damage, and even species) that need to be overcome is rendered manageable by eliminating the first phase in the aging schematic. And since organismal aging can be artificially and reversibly induced by blocking and restarting cellular proliferation, this indicates that the second phase in the model - cessation of proliferation followed by cellular senescence - clearly represents the essential cause of aging. Placing cellular senescence in the pivotal junction between cause and effect, the causal nexus, to yield an integrated model of aging will serve to advance identification of crucial targets for future therapeutic investigation. By identifying cellular senescence as the causal nexus of aging, the process of treating, reversing and possibly even eventually eliminating this once inevitable outcome draws closer to reality.
Layperson thinking here, but surely the Mayo clinic experiments where senescent cells were removed in mice and they still aged and died (just 25-35% slower) contradicts the idea that senescent cells are the central/master/sole driver of aging?
As an aside, it is really nice to have some actual data about all these theories that people have been speculating about for decades.
Hey all !
Intriguing paper. I believe the damages that are the most important revolve around the mitochondria (mtDNA lesions), lysosome (lipofuscin, effete enlarged mitochondrias) and chromosome (telomere loss/lesions y-H2AX foci). AGEs and carbonyls are also very important.
But the most dangerous, cataclysmic and damaging damage is the accumulation/initiation/
propagation of lipid chain peroxidation in mitochondrial innermembrane phospholids fatty acids. This yields lipid peroxidation aldehydes chain products such as MDA-TBARS, MDA-Lys, MDA-CML (CML is an AGEs) and the highly reactive hexanals, alkenals like 4-HNE, 4-HHE and Acrolein.
They damage mitochondrias, mtDNA, ATP production, destabilizing redox (oxidizing shift) and thus, cell's energy metabolism via mitochondrial OXPHOS and ETC respiration.
We can infer that mitochondrial membrane lipid peroxdation kinectics are the most dangerous damages because cells and mitochondrias, during evolution, were faced with a problem of limited cell energy by dysfunctioning mitochondrias; in the face of faulty oxidative phosphorylation (unlike Alternative Oxidase/other mitochondrial Cyanide 'respiration' energy systems), electron leakage in ETC and mitochondrial DNA compromised in antioxidation/nucleotide repair/proximity to mitochondrial lipid innermembrane and outermembrane bilayer/cristae OXPHOS complexes creating mtROS in innermembrane, destroying membrane's phospholipids fatty acids which catalyse lipid peroxidation propagation, yielding said aldehydes who fracture mitochondrial DNA.
Evolution solved that problem by making gene selection pressure on lipidome innermembranes reorganization/substitution of lipid chains composition via gene control of lipid modulation enzymes (phospholipase, desaturase, elongase); by altering unsaturation, double-bond and carbon chain length of polyunsaturated fatty acids towards less peroxidation susceptible ones.
polyunsaturated DHA is 320x times more prone to peroxidation than monounsaturates and saturates. That is massive damage incompatibility with huge lifespans. And, indeed, animals that live the longest have the lowest long-chain polyunsaturated content, the lowest PI (Peroxidizability Index) and DBI (Double-Bond Index). For example, whales such as bowhead whales have lower omega-3 DHA in the heart, and PI, than human hearts. They can live to 211 years old. Same goes for Iceland quahog polar bivalve Arctica Islandica; it lives 508 years and has the lowest PI among short-lived temperate clams who have higher PI, and, thus, exponential accelerated mitochondrial innermembrane peroxdation degradation of both membrane and mitochondrial DNA; thus, basically, the entire mitochondrias are wiped out.
Hi Jim !
That's because they use the umbrella, all-encompassing and vague word 'cell senescence', they do not differentiate overt stress-induced senescence (causing pathologies) from replicative senescence (intrinsic human aging); by using large, loose and vague 'aging' word they do not differentiate pathological aging from intrinsic aging. When they can be appreciably defined, differentiated, classified as different entities - that are part of aging, in the large sens of the word; but that can dissected and divided into different forms of the same aging we are talking about. It's confusion in the semantics and there can be more specificity/precision of it.
I think this article nails it. I think that cells evolved senescence to prevent the error catastrophe that inevitably wipes out populations of clones. Eventually errors in the genes and other assorted problems cause the population to die out. I think evolution's response to this was threefold: 1. it evolved sex to prevent the error catastrophe and 2. in multicellular organisms it evolved senescence to prevent the error catastrophe from creating problematic cells such as cancer.
3. The evolution of stem cells to hold a "reserve" of relatively "youthful" cells that had not gone through many cell divisions in order to replenish tissues when the bulk of the somatic cells in the "colony" had already worn out/gone senescent.
I'd argue, therefore that removing the senescent cells is definitely part of the problem. The other part is how to replenish the "good cells"? Eventually, due to the cloning process all the somatic cells are going to be bad. There's only a limited stock of stem cells. Is there a way to replenish stem cells? Is there a way to "fix" broken somatic cells? One might be easier than the other.
Hey Jim,
There was an earlier comment at https://www.fightaging.org/archives/2016/02/25-median-life-extension-in-mice-via-senescent-cell-clearance-unity-biotechnology-founded-to-develop-therapies.php#comments
that might be of relevance to your question:
"...
while the treatment successfully killed heart, kidney, eye, and fat senescent cells, it failed to kill senescent cells in the colon and liver(and possibly other organs?)
..."
So if that's the case -- then the Mayo Clinic work doesn't disprove this theory (and there are still improvements to be made!)
@Dan the simple answer to that is to restock yourself with stem/progenitor cells periodically. This is as SENS and others have suggested and is a relatively simple process. I have seen as yet unpublished data showing for example MSCs are able to migrate to the brain without the need or intercranial or nasal injection, good news as stem cells could simply be added to the blood stream and they would migrate to where they are needed as they can "home" in on the target area. The trick being improving the engraftment rate of said stem cells when they arrive.
Regards senescent cells being a primary cause of aging, this is unlikely given their accumulation is small to begin with only reaching pathological levels in old age. Far more likely in my view the primary drivers of aging are Telomere attrition, AGE's, Lipofuscin and SASP is just a consequence of that accumulated garbage and dysfunction.
However the best way to test this and other theories is test them. There are over 200 aging theories IIRC, all likely right in some ways and wrong in others. So let us test things and get closer to seeing the elephant!
The thing about Mayo clinic experiment is that they used Mice with defective mitochondria to accelerate the rate of ageing and eliminated senescent cells in them to show comparative effects. Also, not all senescent cells were targetted, the INK-ATTAC strain only had senescent cells with P13Ink4a expressed in high amounts destroyed and not of the whole body, hence susceptibility to diseases of the endocrine system, immune and cardiac failures. A whole comprehensive elimination may change that.
Mayo have released four or five papers on senolytics this is further evidence it is probably a good approach. Our lab will be following up on their small molecule work and adding some additional twists. http://Www.Majormouse.org
“restock yourself with stem/progenitor cells periodically”
Yes, that has been my long term goal. Combine pruning of senescent cells and old stem cells, mobilization of stem cell niches, and replacement with new stem cells in the blood plasma.
Start with fibroblasts; create iPSC culture (resets to fetal developmental “age”); select least damaged iPSCs; genetically engineer iPSCs to remove damage and enhance (gradually replace known bad variants with good variants, may require thousands of modifications); inject enhanced, “young” stem cells into the blood periodically.
The approach might use targeted modulation of the immune system both for pruning cells and for tolerance to gene modifications. Additional treatments involving electromagnetic stimulation and/or drugs and growth factors might be needed temporarily to increase local plasticity for tissue restructuring, e.g., replacement of fibrotic tissue or rewiring neural circuits.
This approach should correct problems with senescent cells, stem cell exhaustion, short telomeres, DNA damage (both nuclear and mitochondrial), and epigenetic drift. As a side benefit my genome would be gradually optimized and then modernized, i.e., regular upgrades to my software.