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 âmechanical senescenceâ: cumulative physical and chemical insults slowly erode irreplaceable structures (think tooth enamel or lens proteins), eventually undermining organ function.
DNA-damage theory
Irreparable lesionsâmutations, strand breaks, cross-linksâsteadily 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 âsoftware,â eroding the cellâs 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 âinflammageingâ) 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 âfuelâ; 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 brainâgonadal 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 âhyper-functionâ (e.g., excess mTOR activity) that damages tissues.
These concise sketches follow the paperâs two overarching categoriesâerror-based mechanisms that stress damage accumulation and program-based ideas that see ageing as maladaptive continuation of developmental programmesâwhile highlighting the distinctive premise of each named theory.
Hereâs 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, youâll 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 doesnât 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. Hereâs 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 ~100Ă higher than plasma because OCTN2 actively accumulates carnitine.
Free carnitine
~11â20 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 â 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 (â2â5 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
â
~20 g stored in a 70 kg adult; endogenous synthesis contributes 11 â 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 ”mol L-1 (range 10 â 50 ”mol 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 â 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 ÎČ-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 98â99 % 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.
Itâs 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 â 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 donât supplement.
That said, I find information loss theory very appealing from conceptual perspective. I believe thatâs what aging is â tissues and cells losing their character over time. Mostly epigenetic. Some genetic as well.
I think it is epigenetic, but the âinformation lossâ theory implies there is a backup copy of the epigenome. We donât know where that is stored which is a good reason to think it does not exist and there is not a âbackup copyâ.
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.