The Futility of Attempts to Rigorously Distinguish Age-Related Disease from Aging
Aging is caused by damage. Age-related diseases are the end result of sizable amounts of that damage, branched out into a network of interacting downstream consequences and system failures. Aging and age-related disease are points on a continuum; age-related disease is an integral part of aging. Yet the predominant way in which researchers and clinicians view aging and age related disease remains one in which an artificial, arbitrary line is drawn between these two things. There is "normal aging" and there is disease. What to make of this when there is very little difference between the level of damage and dysfunction in two people who stand just on either side of that line? Further, the line is subjective, argued over, and interpreted in different ways by different groups, even in fields that apply reliable metrics and a cutoff point.
This business of arbitrary lines is driven by regulation, and the regulation of medicine still proceeds from the basis that aging is distinct from age-related disease - that aging is not a medical condition, should not be treated, is natural, normal, and beyond the bounds of medicine. The result is the present situation, in that regulators such the FDA will grant permission to treat the damage of aging provided that a treatment is only used on one specific tiny part of the constellation of symptoms that result from that damage, and only used for patients who are past a certain point of degeneration, so that their suffering can be stamped with a particular designation. People with a lesser amount of damage, just on the wrong side of the line, are out of luck. It is forbidden to work on prevention by addressing the causes of aging prior to the point at which they and their consequences become very harmful. This is ridiculous, and I think a sizable fraction of the participants in this broken system recognize that it is ridiculous. They nonetheless seem powerless to change it.
This paper on Alzheimer's disease is a fair example of the distracting nature of the dividing line between aging and disease; harmful processes are discounted because they are not harmful enough. Only the exception declines are worthy of note, of treatment. This sort of incentive steers researchers into poor ethical and strategic choices. If the underlying cause of disease, meaning underlying cause of aging, can be addressed, then every older person should be treated, and long before their degeneration becomes threatening to health and mind.
Normal aging is associated with deterioration of cognitive function and accumulation of neuropathological lesions that can also occur in Alzheimer's disease (AD). Distinguishing AD from normal aging, particularly in the earliest stages, allows for more thorough clinical characterization of abnormal cognitive decline and can also provide insights into AD pathophysiology that may ultimately support drug discovery, an element of the AD field that is currently lacking. Since its inception, the amyloid cascade hypothesis has bolstered AD research and helped progress the field immensely, however a fixation on this model may be hindering scientific advances and drug development.
Traditional neuropathological lesions in the AD brain include senile plaques, consisting of aggregated amyloid-β (Aβ) and neurofibrillary tangles (NFT) of tau protein, which accumulate extracellularly and intraneuronally, respectively. Enhanced neuroinflammation is also consistently observed in AD and evidence suggests that early hyperactivity of pro-inflammatory pathways in the brain precedes the development of plaques and tangles in AD. Muddying the waters, however, is the fact that aging itself is associated with similar aberrations in the brain, that may or may not lead to cognitive deterioration. Accumulating evidence suggests that Aβ plaques and neurofibrillary tau tangles are not uncommon in the brains of non-demented, cognitively healthy older people. Evidence has also shown that Aβ deposition correlates poorly with cognitive impairment in elderly cohorts, suggesting that Aβ per se does not directly influence cognitive function.
Classical pathological lesions in AD brain, amyloid and tau deposits are used as measures of disease progression and also as an indicator of therapeutic efficacy. However, given the paucity of consistent correlations between these markers and cognitive decline, future studies may wish to consider alternative pathological measures.