The Distinct Mechanisms of Aging Interact with One Another
Aging has a number of distinct root causes, but they do not proceed in isolation. Cell and tissue damage of one sort interacts with cell and tissue damage of other sorts, and so too do all of the downstream consequences of that damage. Aging is a web of connected issues, all making each other worse as they progress. Degenerative aging accelerates in pace over time precisely because of this behavior, in which damage and dysfunction speeds up the accumulation of more damage and dysfunction. The authors of the open access paper here illustrate this principle by taking mitochondrial dysfunction as a starting point and examining how it interacts with other known mechanisms of aging.
The role of mitochondrial dysfunction in aging is well documented. The primary hallmarks of aging are defined as unequivocally deleterious to the cell. This means that proper functioning of these processes is important for the viability of the cell and the dysfunction that occurs with age leads to cellular damage. Mitochondrial dysfunction interacts with each of these primary hallmarks, thus leading to progression of the aging process.
The nine cellular and molecular hallmarks of aging are divided into three groups; (a) the primary hallmarks, (b) antagonistic hallmarks, and (c) integrative hallmarks. The primary hallmarks, which are unequivocally deleterious to the cell, include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. The antagonistic hallmarks, which are beneficial at low levels but at high levels become deleterious, are deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. Finally, the integrative hallmarks, affecting tissue homeostasis and function, are stem cell exhaustion and altered intercellular communication. These hallmarks of aging have been presented throughout various research disciplines as nine separate hallmarks, and, while possessing crosstalk, are still considered largely independent. In this review, we provide evidence of the interplay between hallmarks, by highlighting one, mitochondrial dysfunction, and how it interacts with all others.
The hallmarks of aging connect to and influence one another. For instance, cellular senescence can be induced by genomic instability or telomere attrition and epigenetic alternations can lead to genomic instability. It is hence evident that the hallmarks of aging are not discrete entities as how are often presented, but instead operate in a large and tightly connected network. Targeting one factor of this network can result in affecting other hallmarks and thus influence the whole network of aging.
Although this complicates our interpretation of anti-aging interventions and requires a more holistic approach, it also opens opportunities for treatment options that not only target one hallmark but in fact act on the entire, or at least a large section of the network. In relation to the phylogenetic tree of life, while the exact details of the hallmarks of aging may differ, the main commonality that unifies aging across all species is the fact that all their hallmarks interconnect. Taking the entirety of this network into account will benefit the aging research community, and ultimately allow for a greater understanding of the aging processes and the progression of age-related disease.
If the crosstalk noxious effects are strong enough to lead to a vicious circle then addressing even a single cause like senecent cells can lead to huge improvements. In a way this is a good news. It means we don't have to fix all the causes to get amazing effects. One well be spectacular on its own and adding another will have a compound effect.
Now the question is with so many systems failing and leading to a vicious circle how come people live longer that 65?
Hi Cuberat, just a 2 cents.
I believe that it is because the threshold to maintain function is kept (despite these systems failing); in other words; organ function, is still functioning (enough) for life. Their health may be compromised (with a disease) - does not mean they die; I had atherosclerosis and coud die of it (as like a disease/affecting my health); but by keeping enough health/above threshold, then you can survive and (even, sort of) 'thrive'...it's not really 'thriving'...it really is 'surviving'..or say 'being decripit'...because you know that if you do fall More ill/more sick, well you may end up below the threshold for organ function/homeostasis...thus, you could obtain premature death (due to a disease).
In reality, we should live about 25 years..not even 65...and that is due to the nucleus/chromosome control of 'pace of aging'; by the loss of telomeric DNA content (and accrual of telomere DNA foci/damage and DNA DSBs/SSBs), our rate telomere of shortening dictates total lifspan/longevity (avg and maximal); and the largest 'pacer' of this pace of shortening is down to mitos ROS emissions (OXPHOS/respiration of O2, causing ROS formation at mitomembrane; (caused mito PUFA lipoperoxidaiton products/membrane pacemaker/homeoviscous lipid oxidaiton theory) which they cause end products that destroy mitos and 'reach' the telomeres/damage telomeres; if telomeres become damaged they accelerate in shortening rate).
Women that lived 115 years, short telomeres in immune cells -> spent all DNA to be spent...no more left...hence the end/Hayflick limit. If you die at 65...it is one of 2 things, your cells most likely left cycle and entered 'premature senescence/spontaneous senescence'..due to excess damage (from a disease for example); or, you accelerated the Hayflick process of aging/you actually 'Aged Faster' (same as like Progeria/HGPS/Hutchison's Gilford Progeria/Werner/Down Syndrome/Trisomy 21), your telomere shortening rate increase substantially and thus you hastened the Hayflick limit. Most disease/inflammation may cause 'premature/spontaneous' exit from the cell cycle - irrespective of the population doubling count (in other words...you did not spend your entire telomeres...your cell exited from the cell cycle - despite still having enough telomeres); but for people who live longer it is oftenly the case that in extreme longevity, the main limiter is not 'premature/spontaneous senescence'...it is Hayflick limit (as like that woman with 3kb size short telomeres in immune cells; it meant that she had reacht the maximum of the possible cell divisions for these cells; and then once that was done; cells would Replicatively Senesce (as they reached Hayflick limit).
Some cells would overcome the limit and continue to divide a litte bit more (hit M1 crisis point; another 'later' barrier...like another point where the cell 'checks itself' to 'die/commit suicide'...and if it continues and overcomes this next barrier..it divides a little more Once more...and then M2 crisis point; the last barrier; this point is Final; and if the cell overcomes this one - it transforms (turns into a rogue cell with cancerous features/ends up a cancerous cell) and may *mmortalize also..because that is the ultimate goal of cancer cells; to *mmortalize as to allow to divide infinitely and 'overtake' the host/body that hosts them. It is mechanism of killing the animal (when compromised/ill/or aged/having done its 'purpose' of making kids and no purpose anymore (biologically, to evolution; well, the grandmother theory refutes that because parenting and lifespan are due to grandmothers making humanity Reach Grand-parent age (by giving grannies longevity genes)); evolution chose that 'removing a bad weed from the garden' is better than letting the garden 'overrunned by compromised/bad weeds'; so, it would kill it/remove it from the pool/specie
because 1 bad weed is all it takes to compromise things (in order to not compromise (not give bad genes/recessive traits/bad health to offspring) the specie/individual's survival; for that is the goal of evolution/it is 'natural selection' Darwin and 'evolving/adapting' the animal to new environments (to make them survive/live (healthily), procreate and prosper as a specie, and a single individual Survivor animal can itself change whole outcome of specie survival (so long as it can find another one and procreate/make offpsrings to continue its legacy/preserve the future of its specie)).
Just a 2 cents.