While Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2D) are two public health concerns in their own right, they are also frequently comorbid; linked by genetics, epidemiology and molecular biology. To date, both diseases are thought to be an inevitability of either modern civilisation or the length of human lifespan. However, a novel hypothesis put forward by Danièlle Gunn-Moore and colleagues in Alzheimer’s and Dementia challenges this view, suggesting that the convergent molecular antecendents to AD and T2D are caused by our post-reproductive longevity, not simply our increasing life span.
The increase in AD and T2D can only be partially explained by the combination of an aging population with increasing sedentary lifestyles and availability of dense caloric foods. The authors alternatively suggest that “…there is a molecular link between longevity and both AD and T2D that suggests a relationship whereby both arise not as an unfortunate consequence of growing older in the modern world but are intrinsic to it.”
If AD and T2D are a product of longevity, then is there a shared mechanism underpinning and unifying all three?
Insulin signaling: the convergent link between longevity, Alzheimer’s and diabetes
The authors postulate that the likely candidate for this unifying link is metabolic impairment, namely impaired insulin function. Insufficient production of insulin and insulin resistance – the failure of beta cells to respond normally to insulin – are central pathophysiological mechanisms in both T2D and AD. However, decreasing the insulin response through the downregulation of insulin signaling may also be the key to increased longevity.
Altering insulin signaling either by knocking out key genes or through caloric restriction has been demonstrated to increase the life span of worms, flies and mice by up to 50%. But before you shun cake altogether, you should know that the increase in longevity was not as large in primates and dogs, although there was still a significant benefit. With the recent increase in fasting-orientated diets it would be very interesting to see if any increase in longevity is observed in humans.
Whilst insulin signaling is inextricably linked to T2D, there is also strong evidence that impaired insulin processing is a large risk factors for AD. Insulin resistance is associated with poorer cognitive scores and predicts amyloid deposition in humans, whereas insulin receptor knockout mice exhibit impaired cognitive performance and increased tau deposition6. Furthermore, the pharmacological enhancement of insulin signalling is associated with a reduced incidence of AD, positively effecting amyloid processing and cognitive performance in early AD. A key molecule implicated in intracellular insulin signalling is glycogen synthase kinase-3 (GSK-3) involved in the regulation of axonal transport, neuronal function and synaptic plasticity. It has been shown that increases in GSK-3 elicits deficits in long-term potentiation and is associated with cognitive impairment and the hyperphosphorylation of tau.
The implication is that the efficiency of insulin processing is central to our longevity and the cost of this longevity is AD. The article predicts that humans’ relatively unique long post-fertility lifespan (PFLS), accounting for more than 40% of our maximal lifespan, is at the heart of both AD and T2D. Our long PFLS is thought to be evolutionary advantageous as explained by the ‘grandmother hypothesis’, along with caramel sweets and stale biscuits. Nevertheless, if there were an interaction between longevity and AD we would expect to find greater evidence of AD pathology in animals with a longer PFLS. To follow this prediction the authors studied dolphins.
Want to read more of our Journal Watch series? Find the full series here, plus highlights below:
- Journal Watch: Protective factors differentially affect amyloid pathology and Alzheimer’s disease-pattern neurodegeneration
- Journal Watch: Lost in propagation – tau induces neuron loss and grid cell dysfunction in transgenic mice
- Journal Watch: Highway to dementia: living near major roads increases risk
Dolphins: a new porpoise?
Dolphins, specifically Stenella coeruleoalba, have an 8% longer PFLS as a proportion of total lifespan compared with humans. The similarities don’t stop there though: dolphins are prone to T2D and we share the same coding region of the APP gene including the Aβ peptide.
However, the observation that an animal could ‘naturally’ exhibit pathological hallmarks of AD is not novel; Aβ plaques are observed in dogs and non-human primates and phosphorylated tau is found in sheep, bison and cheetahs. However, only the dolphin exhibits both AD-like Aβ plaques and neurofibrillary tau tangles.
In a sample of eight dolphins, the authors found three had diffuse amyloid plaques in the parietal cortex and compact plaques in the cerebellum; the latter is very similar to the cortical Aβ aggregates found in humans and was even surrounded by phosphorylated tau deposits. In addition to these sites, neurofibrillary tau deposits were also observed in the thalamus and frontal cortex. However, no behavioral evidence was available to infer cognitive decline.
The authors hasten to state that they do not condone the use of captive dolphins for experimentation but suggest studying the Cetacea ex vivo or in the wild could yield insights into the purported overlap between longevity, AD and diabetes.
“Ironically, only time will tell whether the longevity hypothesis is accurate…”
There is a lot of evidence to support a change in focus away from life span to longevity in AD. Evidence central to this hypothesis comes from insulin signalling, however future research could examine the role of cellular stress (e.g., unfolded protein response) or telomere shortening – both independently implicated in T2D, AD and longevity. Ironically, only time will tell whether the longevity hypothesis is accurate; in the meantime, AD researchers may wish to consider ethological models with a large post-reproductive lifespans such as domesticated dogs or cats.
“If we are right, then it’s too late; we are already long-lived animals and the price we pay is Alzheimer’s disease”. – Gunn-Moore et al.
Review of: Gunn-Moore D, Kaidanovich-Beilin O, Gallego Iradi MC, Gunn-Moore F, Lovestone S. Alzheimer’s disease in humans and other animals—A consequence of postreproductive life span and longevity rather than aging. Alzheimers Dement. doi:10.1016/j.jalz.2017.08.014 (2017).
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- Youssef SA, Capucchio MT, Rofina JE et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet. Pathol. 53(2), 327–348 (2016).