Everyone Ages for the Same Reasons, and Many Age-Related Diseases Share the Same Roots

Mechanically speaking, degenerative aging happens for the same underlying reasons in all of us. We all share the same operation of cellular metabolism, generating the same lingering waste products, the same forms of biochemical wear and tear that slowly slip past otherwise comprehensive repair mechanisms. It's all damage, and aging is in effect just a process of damage accumulation. Our organs and tissues react to that damage and waste in the same ways, so much so that you can use patterns of epigenetic markers of cell state to identify age, pulling that out from all of the thousands of changes in cell state that are distinct to a person's unique environment and circumstances.

There is a lot of interest today in identifying the genetic differences and metabolic processes that react to environmental circumstances to determine natural variations in aging and longevity in our species. Some people think that this is the way to produce therapies to extend healthy life spans: figure out what makes some people more likely to live to 100, say a 1% chance rather than a next to 0% chance, and implement some kind of drug that affects similar changes in ordinary people. Take Human Longevity Inc., for example, as representative of the viewpoint of a sizable research contingent. This all seems like a short-sighted approach to me. You're tinkering around in the reaction to the underlying cause of aging, while failing to address the actual problem - which is the damage that causes these reactions. It's like trying to make cars fall apart less frequently by working on oil formulations. There's a much better approach to making cars fall apart less frequently, and that's to repair them every so often. If you don't carry out periodic repair, you aren't going to get much out of better oil. It all seems backwards in a way.

You can make a bunch of money mining, analyzing, and selling genetic data. Human Longevity Inc. will no doubt do just fine as a business, and along the way add to human knowledge in a useful way that incrementally advances the general state of medicine. This just isn't the path to near term meaningful extension of human life spans. It's heading off in entirely the wrong direction for that, missing the forest for the trees, and the same can be said for much of the rest of the research community. They are very focused on mapping aging and its biochemistry in all of its present variations, and largely disinterested in fixing the damage that causes all of this glorious biological complexity. And pain, and suffering, and death. It's the pain and suffering and death on a vast scale that makes this something other than an academic matter in which the research community can be indulged in their desire to produce a complete map of the situation.

In any case, here is an example of the point that aging has root causes, and many age-related conditions spring from the same root causes. There are thousands of failure modes for damaged tissues, but back down the chain of cause and consequence only a handful of those root causes. This is written from the perspective of those who see intervention in the reactions to damage as the way forward, rather than those who look to repair of damage as the way forward - which is to say it is written from the present mainstream view, not the view that needs to supplant it if we are to see meaningful progress in the near future.

Genetic evidence for common pathways in human age-related diseases

It is widely accepted among gerontologists that common processes mechanistically underlie both aging and the pathogenesis of multiple age-related diseases and that targeting common factors in aging will have a significant benefit to human health. A wealth of experimental data from lower organism studies supports this concept, and human progeroid syndromes indicate that disruption of key biological processes can result in the premature onset of multiple age-related pathologies. There has, however, been little direct evidence that this is true in normal human aging and age-related disease, and the role of canonical aging pathways in human age-related pathologies has not been established.

Our gene-based findings suggest that while inflammation, immune regulation, and cholesterol metabolism are all broadly important in human aging, cholesterol metabolism genes alone are strikingly enriched among multiple age-related diseases. Multiple apolipoproteins have been associated with disease, and APOE is a particularly notable genetic loci in human health, as discussed. Consistent with these prior findings, our data suggest that apolipoprotein metabolism is a key underlying pathway in multiple human age-related diseases. Our findings suggest that apolipoprotein metabolism may represent a mammalian-specific underlying pathway in aging and age-related disease, supporting the notion that interventions in lipoprotein metabolism will provide significant benefits to human health. Epidemiological studies already support the adoption of earlier and more widespread statin use, and least one study has suggested that statins broadly affect the aging process. Clearly, apolipoprotein metabolism warrants continued attention as a safe and efficacious clinical target in aging.

In addition to providing further evidence supporting the critical importance of apolipoprotein metabolism in human age-related disease, here, we provide evidence supporting for the model that common, evolutionarily conserved pathways influence many age-related diseases. The data presented here provide new evidence supporting the continued pursuit of interventions designed to combat age-related disease based on genetic pathways of aging discovered in lower organisms. While many of these pathways, such as genome maintenance and IIS/mTOR signaling, have already been implicated in human health, our study provides the first evidence that genome-wide association studies of age-related diseases show a signature of conserved pathways of aging. Finally, while our study focused on age-related disease, our novel pathway-based approach provides a new method for identifying shared pathways of disease. We anticipate that this approach can be applied to traits that are mechanistically poorly defined to provide novel insight into the pathogenesis of human diseases.


While I do have somewhat higher hopes for HLI, and hope their work can create some type of working treatments... I wish more researchers would start working on a repair based approach sooner rather than later.

Why do you think most researchers don't take the repair/engineering approach? Do you think it's because it's not viewed as "real science", since using the engineering approach would mean they don't have to know every last detail about the metabolism and other processes in order to get results? Or is it because most drugs and therapies so far have been based on tinkering with metabolism and they're familiar with that?

Posted by: Ham at June 19th, 2015 8:14 PM

I agree with your second proposition, that researchers are more familiar with tinkering with metabolism, but there is also the major problem: you cannot, or are at least unlikely to be able to, fix something you don't understand. It's easy to say that aging depends on this or that, but it's not as simple as that. Even young children have the beginnings of cholesterol deposits in their arteries. It will continue to build up throughout their lives and would probably kill them eventually even in the absence of any inflammatory process.

I am certain that there are other "gotchas" elsewhere in the body. The ears grow throughout your life, as does your nose. Probably other things that are more crucial to life do too like parts of heart valves. Similarly waste products accumulate until the burden is unsupportable.

I think that what is really going on in aging is a combination of problems related to the fact that it is easier (faster, cheaper, etc.) to replace something than it is to repair it. Our consumer throw-a-way system has shown us this. This effect is even more evident when you need to keep the object running while you repair it.

The problems are 1) There was no plan for long-term functioning, which means that there are no cellular processes in place to rid cells of small amounts of specific toxins, leading to buildup - evidenced by various amyloidosises 2) The DNA repair mechanisms are not tuned to repair DNA with a low enough error-rate to prevent cell dysfunctions, including cancer. This is evident in the 125 year old woman all of whose white cells were descended from only two cell lines: all the others had become dysfunctional. 3) because of my second point, stem cells, which could probably at least partially solve my first point, become cancerous over time. 4) We are designed to respond to damage with scar tissue or its intracellular equivalent.

These issues mean that in order to treat aging we must 1) find or develop genes that would create a disposal process for toxins and amyloids, and then incorporate it into our cells. 2) Build or find a DNA repair mechanism with a much better error-correcting rate than we currently have. 3) We need to find some way of a) shutting off our current scar-forming healing, and b) create or find a gene complex that would cause full repair to take place.

To the best of my knowledge none of the gene complexes I described above are known to exist. Also, they would represent large numbers of genes that would need to be integrated into our genome, and made to function seamlessly with everything else. We don't know how to do either of these things.

Posted by: Benjamin C Wade at June 21st, 2015 9:26 AM

I don't know if it's as cut and dry as what you suggest we need in order to treat aging. I'm sure it all might play a part in the greater picture, but I'd like to think that some other working interventions (senescent cell clearence, etc) will be possible and effective before we're able to do everything you suggested.

Posted by: Ham at June 21st, 2015 5:02 PM

"Everyone Ages for the Same Reasons, and Many Age-Related Diseases Share the Same Roots"

Yeah a big common link are critically short Telomeres which are the root of so many aging diseases. Not the cause of aging (they shorten from ROS damage and replication etc) but they have been demonstrated to kickstart a load of age related pathologies. See work by Dr Fossel for further elaboration of this.

A possible route to shut off the scar forming healing is P21 gene which has shown promising results in mice. Josh makes a good summary of the work behind P21.


Josh believes we may also find a few key pathways far upstream of the complex mess of metabolism. Telomerase/Telomeres are one example of such an intervention point which whilst not the underlying damage (that is ROS and replication damage) can reverse a significant portion of the consequences in a single hit. Not the SENS way ofc but 9/10 starfish prefer it :)


Posted by: Steve H at June 22nd, 2015 5:55 AM

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