Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances

Abstract

In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.

Fig. 1

Prevalence or incidence of neurodegenerative diseases by age. Epidemiological evidence indicates that ageing is an accelerator of neurodegenerative diseases. The prevalence of AD was based on the data of 2000 in the United States and Europe. The global prevalence of PD was based on the data from 1985 to 2010. The prevalence of ALS was based on the data of 2016 in the United States. The incidence of FTLD was based on the data of 2021 in Europe. AD Alzheimer’s disease, PD Parkinson’s disease, ALS Amyotrophic lateral sclerosis, FTLD Frontotemporal lobar degeneration

Fig. 2

Milestone events in the history of antiageing research. This figure enumerates key events in the field of antiageing research and pivotal advancements in unitizing antiageing strategies to intervene neurodegenerative diseases from the 1930s onwards. NIA National Institute on Aging, ITP Intervention Testing Program, SIR4 sirtuin 4, NAD+ nicotinamide adenine dinucleotide, TOR target of rapamycin, C. elegans Caenorhabditis elegans, AD Alzheimer’s disease, PD Parkinson’s disease

Fig. 3

Overview of integrated systems involved in AD pathogenesis. AD was initially proposed to obey the Aβ cascade hypothesis, with Aβ as its core. Dysregulation of Aβ production and clearance leads to its accumulation, which further induces downstream oxidative stress, NFT formation, neuronal and synaptic degeneration, and ultimately dementia. Here, we propose viewing AD from the perspective of integrated systems. When intense stimulation exceeds the body’s resistance or when the resilience is insufficient to recover from the stimulus-induced disruption, homoeostatic imbalances result, as evidenced by Aβ and tau accumulation, synaptic/neuronal degeneration, and dementia. Genes, the environment and lifestyle are involved at every level. AD Alzheimer’s disease, APP amyloid precursor protein, Aβ amyloid-β, PS presenilin, NFTs neurofibrillary tangles. The figure was produced utilizing the applications Easy PaintTool SAI and Adobe Illustrator

Fig. 4

Schematic diagram of the decline in brain adaptation during ageing and neurodegenerative diseases. a Young and healthy brains can actively respond to various stimuli, thus maintaining homoeostasis and normal brain function. During ageing, the compromised adaptation of the brain is insufficient to recover from stimulus-induced perturbations, resulting in a homoeostasis imbalance and the development of disease. b In the brains of neurodegenerative disease patients, pure neurodegenerative disease pathology is relatively rare and is often accompanied by other pathological changes, such as vascular damage and the aggregation of pathological proteins (e.g., TDP43 and Lewy bodies). Once these comorbidities occur, cognitive decline appears earlier, progresses more rapidly, and reaches lower levels. NDs neurodegenerative diseases, Aβ amyloid-β, BBB blood–brain barrier, NFTs neurofibrillary tangles, TDP43 transactive response DNA binding protein 43. The figure was produced utilizing the applications Easy PaintTool SAI and Adobe Illustrator

Fig. 5

Specific mechanisms by which ageing promotes different neurodegenerative diseases. a Ageing promotes specific neurodegenerative diseases. Ageing is a holistic non-specific process that nevertheless facilitates the emergence of distinct types of neurodegenerative diseases in different individuals. Ageing is co-regulated by both environment and genetic factors (wherein the latter are also subject to environment). As well, ageing exerts an effect on the specific risk factors associated with different neurodegenerative diseases. The interplay between environmental and genetic factors co-regulates ageing, with the latter also being influenced by environmental conditions. Furthermore, ageing impacts the specific risk factors associated with different neurodegenerative diseases. These four aforementioned aspects synergistically interact with the unique mechanisms and pathways underlying neurodegenerative diseases. b Brain ageing acts on the AD pathway. During brain ageing, molecular, cellular, and tissue/systemic networks undergo profound transformations that promote specific pathways conducive to various neurodegenerative diseases. For example, AD is characterized by Aβ accumulation, which occurs alongside age-related comorbidities leading to neuronal degeneration and AD progression. In the context of brain ageing, Aβ-degrading enzymes and amyloidogenic processing of APP directly affect both Aβ production and clearance rates. Key hallmarks of ageing include oxidative stress, mitochondrial dysfunctions, genomic instability, proteasome and lysosomal dysfunctions as well as nutrient perception disorders; these factors collectively enhance Aβ deposition. Additionally, age-related reductions in microglial activity and transport systems such as the blood-brain barrier and glymphatic system impair Aβ clearance efficiency. The accumulation of Aβ triggers downstream formation of NFTs, further exacerbating hallmark features associated with ageing while concurrently diminishing neuroglial support for neurons, this combination accelerates neuronal degeneration linked to AD pathology. Moreover, neuroinflammation along with alterations in structural integrity and functional capabilities within an ageing brain contribute significantly to AD pathogenesis; peripheral organ ageing also plays a role in influencing AD progression through direct effects on Aβ dynamics as well as indirect effects on brain ageing. APP amyloid precursor protein, PS presenilin, ApoE Apolipoprotein E, TREM2 triggering receptor expressed on myeloid cells 2, SNCA synuclein alpha, LRRK2 leucine-rich repeat kinase 2, PINK1 PTEN-induced putative kinase 1, PRKN parkin RBR E3 ubiquitin protein Ligase, SOD1 superoxide dismutase 1, C9orf72 chromosome 9 open reading frame 72, FUS fused in sarcoma, TDP-43 transactive response DNA binding protein 43, MAPT microtubule associated protein tau, GRN granulin, HTT huntingtin, AD Alzheimer’s disease, PD Parkinson’s disease, ALS Amyotrophic lateral sclerosis, FTLD Frontotemporal lobar degeneration, HD Huntington’s disease, NFTs neurofibrillary tangles, Aβ amyloid-β, α-syn α-synuclein

Fig. 6

The impacts of the body‒brain axis ageing on neurodegenerative diseases. The brain interacts with multiple peripheral organs, and the functions and structures of peripheral organs change with age, leading to a decline in their support of the brain. Aged peripheral organs interfere with pathological proteins accumulation, neuronal activity and other brain functions, ultimately promoting the dysregulation of brain homoeostasis and the occurrence of neurodegenerative diseases. FSH follicle-stimulating hormone, Aβ amyloid-β, GCs glucocorticoids, SASP senescence-associated secretory phenotype, AD Alzheimer’s disease, COVID-19 coronavirus disease 2019, NFTs neurofibrillary tangles, APP amyloid precursor protein, PTH parathyroid hormone, FGF21 fibroblast growth factor 21, Gpld1 glycosylphosphatidylinositol-specific phospholipase D1, OCN osteocalcin, LCN2 lipocalin-2, CCL11 C-C motif chemokine ligand 11, B2M β2-microglobulin, GDF11 growth differentiation factor 11, TIMP2 tissue inhibitor of metalloproteinase 2, CSF2 granulocyte‒macrophage colony stimulating factor, PD Parkinson’s disease, α-syn α-synuclein, ALS Amyotrophic lateral sclerosis, HD Huntington’s disease, FTLD Frontotemporal lobar degeneration, ANS autonomic nervous system, RAS renin–angiotensin system. The figure was produced utilizing the applications Easy PaintTool SAI and Adobe Illustrator

Fig. 7

Holistic antiageing strategies. Antiageing strategies need to be implemented systemically at the molecular, cellular, systemic and individual levels. This holistic approach shows promise for preventing brain ageing and treating neurodegenerative diseases. C/EBPβ/AEP CCAAT-enhancer-binding protein/asparagine endopeptidase, IIS insulin/IGF-1 signalling, AMPK 5’-monophosphate-activated protein kinase, SIRT sirtuin, mTOR mammalian target of rapamycin, NAD⁺ nicotinamide adenine dinucleotide, Aβ amyloid-β, CR caloric restriction, MedDiet Mediterranean diet, MIND Mediterranean–DASH intervention for neurodegenerative delay, TRF time-restricted feeding. The figure was produced utilizing the applications Easy PaintTool SAI and Adobe Illustrator