R&R #9: The Collective Contribution of Minor Annoyances
The less sexy aging disorders add up and contribute indirectly to lifespan and chronic disease death rates
While some think of aging as a singular process, I value the itemization that comes with associating it to specific tissues and their related disease indications. One may then easily think of aging as separated on the spectrum between deadly diseases and minor annoyances.
In the first category you have well-known diseases like chronic obstructive pulmonary disorder (COPD), heart failure, chronic kidney disease, non-alcoholic liver disease (NASH)/liver fibrosis, atherosclerosis, Alzheimer’s, diabetes and its respective complications, and of course, cancer (the majority of which are age-related). Called “horsemen of death” (specifically the last 4) by Peter Attia, they are basically the end-stage of aging in various tissues critical for life, and therefor may individually result in death (and collectively cause most instances of human death). They suck up an absurd amount of the collective healthcare spending through medicine cost, monitoring and specialist fees, and hospitalization expenses. Lastly, they are synergistic and worsen each other, in particular diabetes which is sometimes literally seen as an accelerated aging disease.
Causes of death, our world in data.
A close second tier of aging diseases exists which is not directly deadly but is highly visibly disabling, and potentially indirectly deadly. An example is sarcopenia (muscle loss), which was actually recently classified as a disease indication in the ICD-10-CM. While not causing direct mortality (except in special cases like with ALS) it causes indirect mortality by worsening falls and by hastening onset of all of the deadly diseases in category 1 through preventing elderly people from exercising. Another example in this category is immune senescence (weakening of the immune system with aging). It is a main reason the elderly die of pneumonia and sepsis at vastly increased rates, it reduces the bodies ability to target cancer cells, and also contributes to deadly diseases through inflammation. Arguably reproductive system aging also can fall into this category, though it is not directly crippling it is disabling to the dream many people have to have children, and also it has direct negative body-wide health sequelae via menopause/andropause.
But what about less severe aging diseases, affecting sensory or “peripheral tissues”? Those that result in functional loss, but are underappreciated or thought of as “just a natural part of aging”. This includes, for example:
Presbyopia (loss of near vision)
Hearing loss
Osteoarthritis of the knee
Spinal disk degeneration
Bladder problems
Constipation
Skin aging
Sleeping problems
In this article I’ll talk about how each of these have synergistic effects on deadly diseases of aging, directly or indirectly, and about why finding better solutions matters and is a reasonable place to focus resources and attention even for folks purely interested in longevity.
Before going indication-by-indication, let’s just highlight a few very-well studied factors contributing to the deadly diseases of aging, before subsequently pointing out how they can be driven by issues peripheral issues.
Lack of exercise: Exercise decreases your risk of most all chronic diseases. Actual data linked but if you don’t believe it just look at Jack LaLanne.
Social isolation: Increases risk of depression, dementia, as well as physical inactivity/other poor lifestyle choices. Also the main focus of basically all generic article about Blue Zones.
Chronic inflammation: Inflammation directly increases the risk of most all age-related diseases.
Chronic pain: Chronic pain impacts our risk for chronic disease through inhibiting sleep, exercise, increasing stress, damaging mental health/contributing to depression, and even increasing hypertension risk. It also indirectly contributes to the horrible opioid crisis going on as people often start out on legally prescribed opioids.
Now for the disorders themselves.
Presbyopia
This one of course is my favorite as it’s the focus of Lento Bio, my company. Presbyopia is basically the result of the mid-life aging stage of the lens of the eye, whereas the more severe blindness inducing cataracts are the terminal form of aging damage in the tissue. Near vision becomes impossible as the lens is unable to bend and focus light from close sources on the retina due to various forms of protein damage. While restoring flexibility to the lens is the ideal solution (and my focus), existing treatments for most patients involve corrective lenses or, more recently, miotic eyedrops which compensate at the level of the pupil.
Overview of the role of the lens in presbyopia
Literally everyone gets presbyopia, and almost always this happens in the early-to-mid 40s. It would seem like you just pop in some contacts and that’s okay, but the reality is that corrective lenses come with broader risks. Progressive and bifocal lenses, whether contacts or glasses, localize near-vision to a specific part of your Field-of-View (FoV) and thus increase the risk of falls (generally and especially after a diopter change). One friend’s mother I know had this happen while trail running and hurt herself quite bad. Luckily she is still younger and an athlete, but in general falls often provide the link between seemingly innocuous conditions and deadly disease by forcing people into a state of resignation where they cannot exercise and struggle to socialize or work. One could argue that you don’t need reading glasses/lenses while doing physical activity or going up/down stairs, but in the modern age of cellphones people want to be able to read wherever they go.
Visual representation of progressive lens distortion
While this is not a ubiquitous problem, another large issue is that people in low-income countries often have no access to contacts, glasses or an optometrist. In principle reparative treatments could last long and be cheap (especially small molecule based treatments like the one Lento is working on) and could at some point provide an alternative for some of these individuals.
Hearing Loss
Hearing loss with aging can be caused by cochlear hair cell (involved in converting audio signals to brain messages, not the same as the hair on your head) damage, damage to the supply of “endolymph” (fluid in the inner ear), or degeneration of the auditory nerve, often a combination. Symptoms can be partially alleviated by a hearing aid, but can progress to the point that hearing is significantly under functioning even then. Hearing is a large part of people’s connection to the world. While those born deaf have formed communities and lifestyles to compensate for their auditory disadvantage, near-deaf old folks have not. Social isolation often results, both through reduced quality of social interactions due to significant struggle as well as through potentially avoiding social opportunities all together out of defeatism or embarrassment.
Osteoarthritis of the knee
This is actually one of the clearest and easiest connections to make here, to the point that I was considering putting it alongside sarcopenia. Knee pain, first of all, makes exercise much harder as well as falls much more likely. The weight gain likely to result from a drop in physical activity both directly worsens likelihood of getting long-term deadly chronic diseases like diabetes and also exacerbates the original problem as more weight is on the knee. I’ve seen this all play out in a close family member, overall it’s quite a struggle to deal with. The go-to treatment in general is often ibuprofen or other NSAIDs, while knee replacement surgery is an advanced option but is often reserved for severe cases and has issues such as a limited lifetime of use preventing further high-impact activities like running. Better artificial knees and rejuvenation treatment options here would be a game-changer. How are you going to do Parkour when you’re old without good knees?
Spinal disk degeneration
Your spine’s role in well-being has been recognized since ancient times, with Hindu philosophy modeling this concept with the idea of Kundalini energy originating at the base of the spine and several chakras (energy points) existing at various points on the spine. It is objectively a critical connection point between most points of the body and the brain, with the spinal nerves that emanate from the spinal cord to innervate our muscles and organs requiring an intact spinal column to avoid being damaged. Spinal disk degeneration happens to some extent to everyone with aging. Spinal disks are basically a hydraulic cushion between each vertebra, which lose water and volume with aging and thus their ability to cushion, the result of which can be inflammation and damage to the spinal nerves. This can cause lower back pain, the number one cause of chronic pain, which 84% of adults will face.
While disk replacement surgery can be done, you have a lot of spinal disks and generally doing a major surgery for everyone of them is somewhat impractical. Thus alternative ways to rejuvenate them would be very very helpful to older adults. Or we could go full cyberpunk, pulling a David Martinez to replace the entire spinal column (this is another type of nerd that I am). However, not only is this probably not going to be possible until closer to 2077, I also prefer my spinal energy organic if possible.
Bladder/Prostate Problems
As someone whose body is not tuned to hold on to water as is, I don’t look forward to this one at all. Reduced bladder capacity, overactive bladder and urinary incontinence are common in the elderly. Reasons are partly due to intrinsic bladder aging and things like fibrosis, and partly due to aging related dysregulation of the brain/bladder axis. Prostate problems are also often a cause of urinary issues in men. Between 40-50% of elderly patients reported overactive bladder issues at least sometimes, and this was correlated with increased anxiety/depression and multiple Health Related Quality of Life outcomes (notably this is correlation not causation). Underactive bladder is also a huge problem for some with extensive consequences. Bladder issues can worsen sleep due to increased nocturia (waking up to pee) and severe incontinence can make people avoid socializing out of embarrassment, both factors contributing to risk for more severe deadly chronic diseases. While problems with peeing are probably the last thing on most healthy people’s minds, struggling to pee for the 5th time in a night at 4:00am will probably make an artificial bladder seem as exciting as a bionic spine...
Constipation
Chronic constipation is prevalent in almost a quarter of the elderly, with the association of prune juice with old people well-rooted into all of our heads. Causes are more multifactorial than other indications on this list and can include neurologic issues, Irritable Bowel Syndrome (IBS), diabetes, or often as a side effect of medication. In the most severe cases constipation can actually cause deadly disease directly, with fecal impaction or with bowel perforations potentially leading to sepsis. Furthermore constipation is associated with abdominal pain, nausea and cramps, reducing general quality of life.
Skin Aging
“What?” You say. “Skin aging is just a matter of cosmetics! I mean, I’d like to look youthful and healthy, but surely it doesn’t increase my risk of dying”. The truth is, we did not evolve skin purely to look good. It also is the bodies largest organ, and is not without cross-talk with other tissues. Impaired barrier function in aging skin results in inflammation from pathogens intercalating, and this local inflammation increases systemic inflammation significantly. Inflammation then contributes significantly to deadly aging diseases. Reduced ability to produce sweat leads to heat intolerance, which can be deadly specifically for the elderly. And non-healing wounds are a major problem in the elderly as well, they can prevent people from living their life at best and result in sepsis or amputation at worst. Luckily, it is well known that there is a market for inhibition of skin aging, though it is flooded with poor quality science. One therapy that does have a strong scientifically established effect is that of OneSkin, who are also to my knowledge the only skin company deeply intercalated into the longevity community, and their work is really cool.
Sleeping Problems
This is among my largest concerns to be honest. Personally, I become useless with chronic sleep deprivation, with severe inattention and impaired decision making inability, thus I make sure to get at least 7 hours and ideally 8-8.5 hours every night. The elderly have decreased overall sleep (5.8 hours average at age 80 vs 7.5 hours at age 20), and particularly decreased deep sleep (at age 80 just 7.5% of our sleep is spent in deep sleep vs 20% at age 20). Sleep deprivation hugely increases cortisol, reduces insulin sensitivity, and increases inflammation markers like IL-6 associated with aging. Of more interest to many readers of this blog, sleep loss in the elderly is shown to directly drive aging-associated gene expression, senescence and SASP in the elderly. Sleep is required to clear beta-amyloid and other damaging brain waste via the glymphatic system. Reduced sleep can lead to increased risk of obesity and Type-2 diabetes. The causes can be a mixture of idiopathic and secondary to other conditions, but in the end the product of sleep deprivation is a major reduction in one of our bodies most powerful natural methods to rejuvenate itself.
Final Points
This list is non-exhaustive, but it should drive home the point that the “small” things in aging can add up and are synergistic in their effect (just like basically everything in aging), significantly worsening risk of the “big diseases”. If you’re not convinced of the importance of focusing resources and mind-space on these by now, consider a few last points:
1) The vast majority of people who are actually elderly with whom I speak highlight the points above; in fact, this list was largely curated according to points I’ve heard pointed out to me. I trust that if older folks value these issues enough to speak out, then they must matter.
2) A dollar and a minute may just go further when working on a simpler disease. Alzheimer’s has been a multi-billion dollar cash vacuum with a graveyard of failed therapies; this stems in my opinion not only from suboptimal approaches but also from the complexity of the diseases and the tissues themselves. Brains are stupidly complicated, disturbingly fragile, and very hard to reach. On the other hand, bladders are relatively simple and were among the first tissues grown in a lab, lenses are basically just a bunch of primarily inert long-lived protein that need to bend, and skin is sitting there on the surface. I do have confidence that we will have rejuvenation-based or at very least disease modifying treatments for the big diseases soon, but generally I think low-hanging fruits also have intrinsic value for a lot of reasons.
3) These are huge market opportunities. This is what I could find:
Presbyopia therapeutics: $18.2B (US + EU5 + Japan). This is so huge because presbyopia hits everyone in early middle age and thus the patient base is enormous. Also this is a singular indication problem more than anything else in this article so one unicorn therapy could theoretically come to dominate this market.
Hearing Loss: Hearing aid market was $8.9B in 2022, logically rejuvenative treatment market would be a cost-offset and thus somewhat proportional.
Osteoarthritis market: $4.3B world-wide in 2022, but rejuvenative treatments/better replacement therapies could also draw from the $11.7B knee replacement market.
Skin aging market: $40.5B in 2020
4) Wins here are often visible to the average person. Media coverage of aging therapies now is dominated by celebrities who spend millions of dollars and hundreds of hours to look young. There is a primal fascination there. But what happens if in a decade, the average 60 year old is running (not walking) around with no glasses and glowing skin after taking actual, simple therapies? They will talk about it, and people will notice. The more ubiquitous a disorder is, and the earlier onset it is, the more likely you have someone directly in your social network with it and thus the more likely you are to meet your friend/co-worker/etc and be convinced that rejuvenation is possible in a very real sense.
What non-deadly aspect of aging seems worst to you? Which seems not so bad? I would love to hear people’s thoughts in the comments!