Declining mental sharpness “just comes with age,” right?
Not so fast, say geriatrics researchers and clinicians gathered at a prestigious 2018 conference hosted by the American Geriatrics Society (AGS) with support from the National Institute on Aging (NIA).
In a report published in the Journal of the American Geriatrics Society (JAGS), attendees of a conference for the NIA’s Grants for Early Medical/Surgical Specialists Transition into Aging Research (GEMSSTAR) program describe how increasing evidence shows age-related diseases–rather than age itself–may be the key cause of cognitive decline.
And while old age remains a primary risk factor for cognitive impairment, researchers believe future research – and sustained funding – could illuminate more complex, nuanced connections between cognitive health, overall health, and how we approach age.
“We’ve long been taught that cognitive issues are ‘just part of aging,’” explains Christopher R. Carpenter, MD, MSc, who helped coordinate the conference.
“But contemporary medical research shows how bodily changes that lead to diseases like dementia appear long before the symptoms we associate with ‘old age.’
This begs the question:
Is it really age that causes cognitive decline, or is it ultimately the diseases we now associate with age – in large part because we see them with increasing frequency now that we live longer?
That’s what we wanted to tackle coming together for this meeting.”
Hosted by the AGS and NIA in 2018 as the third conference in a three-part series for GEMSSTAR scholars, the NIA “U13” conference brought together NIA experts and more than 100 scholars, researchers, and leaders representing 13 medical specialties to explore experiences with cognitive impairment across health care.
Conference findings, published in JAGS (DOI: 10.1111/jgs.16093), detail early thinking on the two-way relationship between cognitive health and the health of other organ systems, as well as opportunities for moving science and practice forward.
And while old age remains a primary risk factor for cognitive impairment, researchers believe future research – and sustained funding – could illuminate more complex, nuanced connections between cognitive health, overall health, and how we approach age. The image is in the public domain.
According to attendees, several themes emerged:
- Researchers and clinicians from across health care noted the critical relationship between two of their top concerns: Dementia and delirium (the medical term for abrupt, rapid-onset confusion or an altered mental state, which affects millions of older adults annually). Research now suggests delirium and dementia are mutually inclusive risk factors, with cases of one prompting risks for the other. Thus, prevention of delirium may offer the unprecedented opportunity to prevent or lessen future cognitive decline.
- Still, as one of the conference attendees noted, “[T]he brain is not an island.” Because the conference focused on the impact of cognitive impairment across specialties, a critical focal point for scholars was the complex, bi-directional relationship between cognition and the rest of the body. Cognitive impairments can serve as indicators or influencers in the course of other diseases and conditions. For example, cognitive impairment is perhaps “the strongest independent predictor” of hospital readmission and mortality for older people living with heart failure.
- As the field progresses, however, a major barrier remains: A dearth of research owing to the exclusion of potential study participants who are cognitively impaired. Though obtaining informed consent (the term used to describe a person’s willingness to participate in a study after confirming they understand all the possible risks and benefits) remains challenging, researchers pointed to data that willingness to participate remains high. Coupled with suggestions for tailoring consent safeguards to the types of studies and potential participants thus holds promise for protecting against exploitation while continuing to move cutting-edge care principles forward.
As the GEMSSTAR conference attendees concluded, “The aging of the U.S. population and the growing burden of dementia make this an area of critical research focus…[U]nderstanding and addressing cognitive health and its relationship with the health of other organ systems will require multidisciplinary team science…[and new] study designs…”
Funding: Funding for this conference was provided in part by the National Institutes of Health (NIH, Award Number U13AG048721). The information and views expressed in conference materials and this release are solely the responsibility of the authors do not necessarily represent the official views of the NIA and/or the NIH.
Aging and Pathologies Share the Same Common Mechanisms
The longstanding question if old age is itself a disease has been addressed since ancient times, starting from the Roman playwright Terentius, who claimed “senectus ipsa est morbus” (old age itself is a disease), and Cicero who some decades later argued in De Senectute: “pugnandum, tamquam contra morbum sic contra senectutem” (we have to fight against aging, as we do against a disease).
These quotations elegantly summarize a long-held view of aging and old age addressed by several scholars (see Appendix for further details).
Notwithstanding, with the birth of modern medicine in the nineteenth century, this old tenet has been somehow put apart, as the main interest at that time was to define precise medical entities (diseases and syndromes) and their causes (infections, genetics, degenerative processes, inflammation, etc.).
This process ended up in considering aging and diseases as separate phenomena that could eventually interact but that are essentially different in nature.
In this review, we will reappraise and challenge the old tenet that aging and age-related diseases (ARDs) and geriatric syndromes (GSs) are separate entities, and we will suggest instead that both should be considered as parts of a continuum.
To support this hypothesis, we will highlight that aging and ARDs/GSs share the same basic molecular and cellular mechanisms.
Aging is the predominant risk factor for most diseases and conditions that limit healthspan. Accordingly, interventions in animal models that end up in an extension of lifespan prevent or delay many chronic diseases.
Why?
For many years the explanation was that aging per se is a physiological condition, which favors the onset of many diseases. However, their relationship is likely much more complex, and a major reason is because they share the basic mechanisms.
Assuming that aging and ARDs/GSs share the same mechanisms, which are commonalities and differences? In this review, we will argue that an integrated hypothesis, fitting most epidemiological and experimental data, is to consider ARDs/GSs as an acceleration of the aging process.
The conceptualization of accelerated aging started from the observation of rare genetic disorders (1), including Hutchinson–Gilford progeria (2), mandibuloacral dysplasia (3), Werner’s syndrome (4), and aneuploidies such as Down syndrome (DS) (5).
Here, we extend the concept of acceleration of aging to those members of the general population undergoing ARDs and GSs, in comparison with a small minority of people, such as centenarians, who reach extreme age largely avoiding or postponing most ARDs/GSs.
This consideration is reinforced by the observation that among centenarians there are few subjects who never suffered of any overt ARDs.
These exceptional individuals can be taken as a proof of principle that “healthy” aging and diseases can occur separately, as phenotypes at the extreme of a continuum, which is fueled by a common set of molecular and cellular mechanisms.
Which are the basic mechanisms shared by aging and ARDs/GSs?
A group of international experts identified “seven pillars” which actually include adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, epigenetic modifications, and inflammation (6).
Many chronic diseases and pathological conditions (listed in Table Table1)) are at least in part determined by (some of) these mechanisms, as it will be detailed in the next paragraphs, lending support to this hypothesis.
Table 1
Age-related pathologies and molecular relationship with aging.
| Age-related pathology | Mechanisms shared with aging process | Markers | References/reviews |
|---|---|---|---|
| Alzheimer’s disease | Inflammation Oxidative stress Mitochondrial dysfunction Decreased proteasome activity Cellular senescence Gut microbiota alterations | IL-6, TNF-α, IL-1β, TGFβ, IL-12, IL-18, and INFγ 8-hydroxyguanosine, 8-hydroxy-2′-deoxyguanosine, oxidized proteins, and lipid peroxidation 20S core reduced activity Presence of senescent cells Activation of pro-inflammatory cytokines, increased intestinal permeability | (7) (8) (9) (10) (11) (12) |
| Cancer | Inflammation Cellular senescence | IL-6; presence of senescent cells | (13–16) |
| Chronic obstructive pulmonary disease | Telomere shortening Oxidative stress Cellular senescence Inflammation, inflammasome; activation of NLRP3 Activation of PI3 kinase–mTOR signal Dysregulated nutrients sensing; loss of proteostasis autophagy mitochondrial dysfunction Stem cell exhaustion | p21CIP1/WAF1, p16INK4a, β galactosidase activity, and senescence-associated secretory phenotype IL-1β, IL-6, IL-18, chemokines (CXCL8 and CCL2), metalloproteinases Stress markers such as Parkin and phosphatase and tensin homolog-induced protein kinase 1 | (17, 18) |
| Maculopathy | Chronic retinal inflammation, dysregulation of autophagy, accumulation of oxidative stress-induced damage, protein aggregation, and lipofuscinogenesis | Heat shock proteins; Abs vs self-epitopes; and inflammasome activation | (19, 20) |
| Osteoarthritis | Cell disruption; cellular senescence; mitochondrial dysfunction and oxidative stress; and reduced autophagy; inflammation | HGMB1; HGMB2; and IL-8 | (21) |
| Osteopenia/osteoporosis | Chronic inflammation | TNF-α; IL-6; CRP; and inflammatory markers | (22) |
| Parkinson’s disease | Inflammation Cellular senescence Gut microbiota alterations | Presence of inflammatory cells (astrocytes) and senescent cells Activation of pro-inflammatory cytokines, increased intestinal permeability, and alteration of the serotonin system | (23) (24) (25) |
| Periodontitis | Inflammation | Porphyromonas gingivalis express peptidylarginine deiminase generating citrullinated epitopes Pro-inflammatory cytokines | (26) |
| Rheumatoid arthritis | Cell death and chronic inflammation | Abs vs modified self-epitopes; HGMB1 Matrix metalloproteinases TNF-α; IL-1β; and IL-6 | (27) |
| Sarcopenia | Inflammation and oxidative stress | Elevated levels of TNF-α, IL-6, IL-1, and CRP | (28–30) |
Following this idea, the very difference between aging and diseases would relay on the rate/speed and intensity of aging cellular and molecular processes, combined with specific organ/systems genetic and lifestyle/habit predisposition.
Thus, on the long run, all the functional domains undergo a physiological decline that eventually can lead to overt clinical diseases, favored by organ/system-specific genetic and environmental factors.
This progressive path generates a continuum between the healthy juvenile status and the impaired unhealthy elderly one.
Accordingly, all major ARDs/GSs are characterized by a long subclinical incubation period, where the diagnostic signs of diseases are largely unobservable due to the high operational redundancy of biological systems.
This redundancy, together with the progressive capacity of cells and systems to adapt (“remodeling theory of aging”) (31, 32) is capable to buffer the progressive accumulation of molecular damages, thus hampering the availability of objective early diagnostic signs/tools.
As an extreme example in neurodegenerative diseases such as Parkinson’s disease (PD), it is possible to ascertain advanced anatomopathological alterations in the absence of any specific clinical symptoms in patients died of other diseases.
Accordingly, aging on one side and ARDs/GSs on the other have to be considered different trajectories of the same process but with a different rate depending on diverse genetic background and lifestyle (33–35).
Some considerations can help the reasoning on this topic: (i) aging has not been selected during evolution, and no gerontogene has been identified so far, i.e., no gene has been apparently selected with the precise purpose to trigger/cause the aging phenomenon, thus leaving a large space for stochasticity (36); (ii) genetics and environment interact with each other to determine the eventual phenotype.
These two considerations can explain (a large part of) the heterogeneity of phenotypes observed in aged persons.
Actually, the primary aim of a gene (or group of genes) is always devoted to increase the survival or reproductive fitness of the organism, and aging could be an unpredicted byproduct of its basic function.
Following this idea, some years ago Mikhail Blagosklonny and Michael Hall proposed that aging could be conceptualized as a sort of dysregulated continuation of the normal developmental process and related cellular “programs,” with particular emphasis on mTOR-driven growth (37, 38).
According to this theory, overactivation of signal transduction pathways and exacerbation of normal cellular functions such as growth, leading to alteration of homeostasis, malfunction, and organ damage are likely the driving forces of the aging process including the onset of ARDs. This theory complements the “inflammaging” theory of aging (39).
Inflammation is among the aforementioned “seven pillars,” and inflammaging is defined as the chronic, low-grade (subclinical) and sterile inflammation that is observed in old persons.
It is caused by increased stimulation of innate immune system by “non-self” (persistent infections), “self” (cell debris, nucleic acids, glycated proteins, etc.), and “quasi-self” [gut microbiome (GM)] components of our body as a meta-organism, and by accumulation of senescent cells characterized by a pro-inflammatory secretory profile (40, 41).
Thus, both the overactivation and inflammaging theories agree that programs selected for development and survival (inflammation) can turn detrimental when continue to be active unabated for a period time longer than that predicted by evolution. The same can apply for other programs of the abovementioned “seven pillars.”
Source:
American Geriatrics Society
Media Contacts:
Daniel Trucil – American Geriatrics Society
Image Source:
The image is in the public domain.
Original Research: Open access
“Impact of Cognitive Impairment Across Specialties: Summary of a Report From the U13 Conference Series”. Christopher R. Carpenter et al.
Journal of the American Geriatrics Society. doi:10.1111/jgs.16093
