Ageing is a complex biological process whose underlying mechanisms remain contentious. Nonetheless, due to an ageing global population and the rising incidence of age-related diseases, understanding why we age is one of the most important scientific questions of our time, with profound medical implications. Here, I explore the fundamental nature of the ageing process and provide an overview of modern mechanistic theories. I critically examine two main groups of ageing theories: error-based and program-based theories. I discuss the relevance of these theories in the context of ageing patterns, genetic manipulations and longevity drugs, highlighting how experimental challenges and technological limitations have hindered progress. Overall, there is a pressing and unmet need for a robust theoretical framework in ageing research. Elucidating the cellular and molecular mechanisms of ageing would be crucial for developing effective interventions that slow the ageing process and prevent its associated diseases.
Sadly this is behind a paywall, but I have a copy which copyright law prevents me uploading, but I can post a summary via o3.
Contemporary theories of ageing discussed in the paper
Theory
Essence in ~2 sentences
Wear-and-tear
Ageing reflects passive “mechanical senescence”: cumulative physical and chemical insults slowly erode irreplaceable structures (think tooth enamel or lens proteins), eventually undermining organ function.
DNA-damage theory
Irreparable lesions—mutations, strand breaks, cross-links—steadily build up in the genome, distorting gene expression and triggering cell dysfunction that scales up to organismal ageing.
Free-radical theory
Reactive oxygen species produced by metabolism oxidise DNA, lipids and proteins; imperfect antioxidant defences let this oxidative damage accumulate and drive physiological decline.
Telomere shortening
Protective chromosome ends shorten with each cell division; once they reach a critical length, cells enter senescence or apoptosis, limiting tissue renewal and promoting age-related degeneration.
Mitochondrial theory
Damage to mitochondrial DNA and membranes impairs ATP production and increases ROS leakage, creating an energy-deficit/oxidative vicious cycle that contributes to systemic ageing.
Protein-damage / loss-of-proteostasis
Mis-folded, oxidised or cross-linked proteins escape quality-control systems, aggregate or malfunction, compromising cellular homeostasis and tissue integrity over time.
Epigenetic drift
Age-linked, stochastic changes in DNA methylation and chromatin marks alter gene-regulatory programs, gradually pushing cells away from optimal states and fostering dysfunction.
Error-catastrophe
Transcription or translation mistakes yield faulty proteins that in turn exacerbate information-processing errors in a self-amplifying loop, culminating in cellular failure.
Information-loss theory
Viewed broadly, accumulating errors (genetic, epigenetic, mitochondrial, etc.) represent a progressive loss of biological “software,” eroding the cell’s capacity to maintain order.
Dysdifferentiation hypothesis
Cells progressively lose their specialised identities, drifting toward less-differentiated states; tissue architecture and function deteriorate as a consequence.
Cellular senescence theory
Stress-induced, replication-limited cells cease dividing but secrete pro-inflammatory, matrix-remodelling factors; their accumulation disrupts tissue micro-environments and accelerates ageing.
Stem-cell exhaustion
Age-related quantitative loss and qualitative decline of stem cells reduce regenerative capacity, leading to impaired tissue maintenance and functional decline.
Immunologic theory
Progressive immune dysregulation (immunosenescence + chronic “inflammageing”) undermines host defence and fosters multi-organ damage, making it a system-wide driver of ageing.
Energy-consumption hypothesis
Organisms may have a finite reserve of a vital metabolic “fuel”; usage over the life course depletes this stock, eventually limiting physiological performance.
Rate-of-living theory
A macro-level corollary of the above: species (or individuals) with higher mass-specific metabolic rates supposedly age faster because they accumulate damage more quickly. Though attractive historically, empirical support is weak.
Neuroendocrine theory(program-based)
Ageing is hormonally orchestrated: the same brain–gonadal signalling axes that govern growth and reproduction also set the pace of later-life decline via endocrine programmes.
Ageing is a quasi-programme: developmental and growth pathways keep running when they are no longer needed, driving late-life “hyper-function” (e.g., excess mTOR activity) that damages tissues.
These concise sketches follow the paper’s two overarching categories—error-based mechanisms that stress damage accumulation and program-based ideas that see ageing as maladaptive continuation of developmental programmes—while highlighting the distinctive premise of each named theory.
Here’s the list as a list:
Wear-and-tear
DNA-damage theory
Free-radical theory
Telomere shortening
Mitochondrial theory
Protein-damage / loss-of-proteostasis
Epigenetic drift
Error-catastrophe
Information-loss theory
Dysdifferentiation hypothesis
Cellular senescence theory
Stem-cell exhaustion
Immunologic theory
Energy-consumption hypothesis
Rate-of-living theory
Neuroendocrine theory (program-based)
Software-design-flaw / Hyperfunction theory (program-based)
and a link to the chatGPT exposition (the same as the above for now, but I may add to it)
To me, it seems that aging is a blend of most of those theories, with each theory contributing a varying amount to total aging. To get true longevity increases, you’ll need to work on each area since when you improve in one area, another may become your weakest link and therefore limit your lifespan.
For instance, for most people, the weakest link is cardiovascular. It doesn’t matter how long your telomeres are if you drop dead from a coronary.
I wonder if we can rank these in a hierarchy of importance? As in, which ones limit us before others as in my example above. Probably this would be based on the most prevalent causes of death - Cardiovascular, Cancer, COVID, and COPD.
Aubrey de Grey made a good point that there are strong theories of aging (which limits the source to a small number of defined causes) and weak theories that point at lots of different things.
I go for a strong theory linked primarily to mitochondria and secondarily to the presence of senescent cells both of which operate through acetylation to create the phenotype. That makes working out synergistic interventions easier.
@John_Hemming I do believe that mitochondria are a key driver in healthy aging, and, once cardiovascular disease is mitigated, probably one of the largest limiting factors in lifespan. It would be very interesting to see what the mitochondrial health of supercentenarians is!
Have you considered using Lysine to improve mitochondrial health? I may have missed it if you had mentioned this earlier. The reason I ask is that carnitine is supposedly excellent for mitochondria ,and it is created from lysine and methionine. Since methionine restriction is also excellent for longevity, I am wondering if Lysine would kill two birds with one stone.
From AI, so beware of hallucinations. It sounds reasonable to me, but I am not an expert on Carnitine.
Carnitine plays a crucial role in mitochondrial health, primarily by facilitating the transport of long-chain fatty acids into the mitochondria, where they are oxidized for energy production. Here’s a breakdown of its mechanism:
1. Fatty Acid Transport
Carnitine Shuttle: Long-chain fatty acids cannot cross the mitochondrial membrane directly. Carnitine binds to these fatty acids, forming acylcarnitine, which can then be transported into the mitochondria.
2. Beta-Oxidation
Once inside the mitochondria, acylcarnitine is converted back to fatty acids, allowing them to undergo beta-oxidation. This process breaks down fatty acids into acetyl-CoA, which enters the Krebs cycle for ATP production.
3. Energy Production
The ATP generated from fatty acid oxidation is essential for various cellular functions, supporting overall mitochondrial health and function.
4. Antioxidant Properties
Carnitine has been shown to have antioxidant effects, helping to reduce oxidative stress within mitochondria, which can lead to improved mitochondrial function and decreased cellular damage.
5. Role in Metabolism
Carnitine also plays a role in carbohydrate metabolism and may help regulate glucose levels, further supporting cellular energy needs.
Summary
By facilitating fatty acid transport, enhancing energy production, and providing antioxidant protection, carnitine is vital for maintaining mitochondrial health and function. This contributes to overall metabolic efficiency and cellular energy balance.
Concentration is ~100× higher than plasma because OCTN2 actively accumulates carnitine.
Free carnitine
~11–20 mmol kg-1 dry weight at rest; fatigue sets in when levels fall toward ~6 mmol kg-1 dry weight during intense exercise. (pmc.ncbi.nlm.nih.gov)
Acetyl-carnitine
~0.5 mmol kg-1 wet at rest, rising to 3 – 4 mmol kg-1 wet immediately after exhaustive exercise before returning to baseline within ~3 h. (pmc.ncbi.nlm.nih.gov)
Heart, kidney, other high-oxidative tissues
Total carnitine also sits in the low-mmol kg-1 wet range (≈2–5 mmol kg-1), broadly similar to skeletal muscle, reflecting high fatty-acid oxidation demand. Data are scarcer but follow the same order-of-magnitude pattern as muscle. (cris.maastrichtuniversity.nl)
Whole-body pool
—
~20 g stored in a 70 kg adult; endogenous synthesis contributes 11 – 34 mg day-1, with the remainder coming from dietary intake and renal conservation. (en.wikipedia.org)
Age-related variations
Newborns/infants: Mean plasma free carnitine around 25 µmol L-1 (range 10 – 50 µmol L-1), rising gradually through childhood. (article.imrpress.com)
Pregnancy: Maternal free carnitine typically falls by ~30 % late in gestation because the fetus accumulates carnitine; cord-blood values are often at the upper adult range.
Elderly: Slight declines in muscle carnitine (~10 – 15 %) have been reported, partly attributable to diminished OCTN2 transport and synthesis.
Practical take-aways for interpretation
Look at both absolute free carnitine and the acyl-/free ratio: low C0 with a high ratio (> 0.4) is more specific for impaired β-oxidation than C0 alone.
Muscle biopsy values are orders of magnitude higher than plasma; therefore, modest shifts in plasma can mask substantial intracellular deficits.
Exercise, high-carbohydrate feeding or insulin infusion transiently raise muscle acetyl-carnitine, buffering acetyl-CoA and facilitating pyruvate dehydrogenase activation.
Renal function matters: the kidney reabsorbs 98–99 % of filtered carnitine. Even mild renal impairment can elevate plasma levels without reflecting tissue sufficiency.
These ranges provide the physiologic yard-stick for diagnosing primary carnitine deficiency, secondary depletion (e.g., organic acidemias, long-term valproate therapy), or, conversely, for interpreting plasma elevations seen in renal failure or high-dose supplementation.
The question, therefore, is what effect supplementation has. It might be like creatine. Creatine can be useful to supplement, but the body creates some anyway. Whether it has any particular role in protecting mitochondrial DNA and/or reducing ROS is another issue. That appears on your list.
It’s important to note, however, that L-carnitine supplements may raise your blood levels of trimethylamine-N-oxide (TMAO) over time. High levels of TMAO are linked to an increased risk of atherosclerosis — a disease that clogs your arteries.
More studies on the safety of L-carnitine supplements are needed.
So, something that may be good for your mitochondria may be bad for your cardiovascular system. Or at least it raises another issue that needs to be addressed (TMAO levels).
My own view is that there is not good evidence that it moves the needle to supplement. Hence I personally am not worried about any negative effects of supplementation because I don’t supplement.
That said, I find information loss theory very appealing from conceptual perspective. I believe that’s what aging is – tissues and cells losing their character over time. Mostly epigenetic. Some genetic as well.
I think it is epigenetic, but the “information loss” theory implies there is a backup copy of the epigenome. We don’t know where that is stored which is a good reason to think it does not exist and there is not a “backup copy”.
My view is that it links to the development clock being the same as the aging clock and the epigenetic expression of any one cell links to where its clock is set. (which is the average efficiency of mitochondria). This is also affected by SASP, however, which is a secondary feedback system.
The video presents a new physics-inspired model of aging, focusing on resilience, randomness, and biological clocks.
Here are the key points from the discussion between Dr. Matt Kaeberlein and physicist Jan Gruber:
1. Aging as Loss of Resilience
Aging is described as a gradual loss of the body’s resilience to random, stochastic (random) events and stressors. As we age, our physiological systems become less able to return to equilibrium after being perturbed, making us more vulnerable to disease and death.
2. Physics-Based Model: Potential Wells and Stochasticity
Gruber uses a physics analogy: the body’s physiological state is like a ball in a potential well. When young, the well is deep (high resilience), but it becomes shallower with age (lower resilience). Random fluctuations (noise) can push the system out of the well, leading to failure (death). The probability of this happening increases exponentially as the well gets shallower.
3. Two Key Parameters Define Lifespan
The model proposes two main factors:
The rate at which the “potential well” becomes shallower (damage accumulation/aging rate).
The “temperature” or level of stochastic fluctuations (randomness) in the system, which is species-specific and may be influenced by genetics and environment.
4. Genetics, Environment, and Lifestyle
Both genetics and environment (including lifestyle) influence the rate of damage and the likelihood of stochastic events. For example, lifestyle choices like diet and sleep can modulate the risk of damage events.
5. Biological Age and Measurement
Biological age is best measured by assessing the system’s resilience—how quickly and completely it returns to equilibrium after a challenge. This requires longitudinal data and dynamic measures, not just static biomarkers like methylation clocks.
6. “Enslavement” and System Collapse
When one physiological system loses resilience, it can drag others with it, leading to a cascade of failures—similar to how a crisis in one part of society can affect the whole.
7. What Epigenetic Clocks Measure
Epigenetic clocks capture both random (stochastic) changes and correlated changes due to system failures. Current mathematical techniques struggle to separate these two signals.
8. Animal Models and Human Aging
Many interventions that extend lifespan in animal models may not translate to humans, partly because short-lived species may always be in an unstable state, making them poor models for human aging.
9. Utility of Longevity Clocks
For a biological clock to be useful, it must predict individual outcomes (like disease or mortality) and be actionable for interventions. Large, real-world studies are needed to validate these clocks.
10. Future Directions
Gruber is excited about integrating different types of data (clinical, proteomic, wearable devices) to create more accurate, actionable aging clocks and to test interventions that could improve healthspan and resilience.
There’s an unusual theory I heard about watching one of Michael Lustgarten’s videos a while back that could be considered part of the “wear and tear theories of aging”, called “autodigestion” (which I guess has been posted possibly multiple times to this forum):
As I recall (has been a while since I’ve seen it), one aspect of this is that, over time, the intestinal lining wears down, and then this permits digestive enzymes and bacteria and other things to enter the blood, where they can reach and degrade the extracellular matrix. Keeping the gut lining strong might counteract this, and there are lots of claimed methods for how to do this.
One of these is simply to supplement with AKG, though I think there aren’t many human clinical trials yet on this (or any at all) – currently, they are mostly in mice and rats (and maybe farm animals). e.g. there is this:
“We gave the mice alpha-ketoglutarate, and it was amazing to see how much their tissue was able to heal itself,” Dr. Chaves-Perez adds.
The video explores how autodigestion by digestive enzymes may drive aging and organ damage.
Key Points from “Aging By Autodigestion: Geert Schmid-Schöenbein, PhD”
Autodigestion Hypothesis: Dr. Geert Schmid-Schöenbein presents the idea that aging is significantly impacted by autodigestion—where digestive enzymes, especially from the pancreas, escape the gut and begin to digest the body’s own tissues.
Digestive Enzymes and Aging: While there are thousands of studies on aging, almost none have explored the role of digestive enzymes in this process. Dr. Schmid-Schöenbein’s lab is pioneering this research.
Experimental Evidence:
In animal models, plasma from non-survivors of shock activates immune cells, suggesting harmful factors in the blood.
The pancreas is identified as a major source of these harmful stimulators, with digestive enzymes being the main culprits.
When digestive enzymes leak into the bloodstream, they degrade plasma proteins, surface receptors (like insulin receptors), and extracellular matrix, leading to organ dysfunction and potentially death.
Protective Mechanisms:
The body uses protease inhibitors (produced in the liver) and a mucosal barrier in the gut to prevent digestive enzymes from escaping into the body.
Aging is associated with a breakdown of these barriers, allowing enzymes to infiltrate organs such as the liver, lungs, heart, brain, and skin.
Consequences of Enzyme Leakage:
Enzyme infiltration is linked to the breakdown of collagen and other structural proteins, contributing to tissue aging and organ dysfunction.
This process is observed uniformly across organs in aged animals.
Diet and Lifestyle Factors:
High-fat meals and alcohol can damage the mucosal barrier, increasing the risk of enzyme leakage.
Calorie restriction and time-restricted eating may reduce the risk by allowing the gut barrier to repair itself between meals.
Potential Biomarkers and Interventions:
Elevated protease activity in blood could serve as a biomarker for risk.
Protease inhibitors (like alpha-1 antitrypsin) and new technologies to measure enzyme activity are being explored as possible interventions.
Future Directions:
The lab is working on ways to block digestive enzymes outside the gut without impairing digestion, potentially slowing aging and reducing disease risk.
In summary, the video proposes that the escape of digestive enzymes from the gut is a major, underappreciated driver of aging and organ damage, and that maintaining gut barrier integrity and controlling enzyme activity could be key strategies for healthy aging.
