Understanding Normal Brain Aging

The rise in life expectancy together with decreasing replacement fertility is causing rapid aging in western societies. In Germany, for example, 47% of the population is expected to have an age of 50 + already in 2035. The resulting societal challenges are manyfold, including changes in consumption patterns, patterns of work and retirement, healthcare issues, and the prevalence of chronic diseases and disabilities. 

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Among the latter, mental health is of paramount importance. Indeed, already “healthy” or “normal” aging is accompanied by an age-dependent cognitive decline. Moreover, many older adults experience mental disorders, including but not limited to depression, anxiety, or dementia. Therefore, an in-depth understanding of physiological changes that occur during brain aging is crucial. 

This issue of Pflügers Archiv—European Journal of Physiology provides a series of review articles and original papers focusing on diferent key aspects of (patho)physiological brain aging including changes in energy provision [8], the age-dependent accumulation of reactive oxygen/ nitrogen/carbonyl species [8, 14], aging of the brain vasculature including the key glial cells involved [2, 17] as well as age-related decline in brain wiring [6, 13, 16, 17] and network function [4, 6]. 

Moreover, we focus on the two sensory systems (hearing and olfaction), prone to significant age-related deterioration. The latter is well known to predict (olfaction) or promote (hearing) mental decline [12, 15]. Physiological aging is associated with several challenges to brain homeostasis including the intensification of oxidative stress, compromised bioenergetics, increased levels of pro-inflammatory substances, low-grade immune activation, modified functional properties of main immune cells of the drain, changes in the glymphatic system (responsible for the life-long waste collection), vascular aging, and arterial stiffness, etc. [2, 5, 8–10, 14, 17]. Moreover, hypersynchrony of neuronal networks also represents a key feature of brain aging [1, 6, 7, 11, 15]. 

This imposes demands on the vascular system, supposed to match an increase in cerebral metabolic activity with an increase in cerebral blood flow, thus ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity [2]. At the same time, the aging brain possesses remarkable resilience and adaptivity, allowing it to cope with the listed above problems. Indeed, already one of the very first epidemiologic studies, which was published in Cambridge in 1889 and included 900 oldest old (80 + years of age, 74 centenarians), concluded that the brain is preserved much better than many other physiological systems and represents one of the highlights “in the centenarian landscape” [17]. 

In this issue, we review the cellular and molecular mechanisms underlying key physiological adaptations enabling the aging brain to mitigate age-related functional and structural decline. We also mention that lifestyle changes (i.e., intellectual engagement, physical exercise, healthy diet, and caloric regime), help to increase the cognitive reserve. 

Although aging per se is not considered a disease, it is a major risk factor for cerebrovascular (e.g., stroke) and neurodegenerative (e.g., diferent kinds of dementia) diseases, which are associated with high morbidity and mortality [2, 3, 15]. Hearing loss may also lead to social isolation, depression, and a decline in cognition [12]. The comorbidity of cognitive and sensory impairment is not rare [1, 12]. 

Together, Alzheimer’s (AD) and Parkinson’s (PD) diseases represent the most common forms of dementia. Interestingly, both pathologies are accompanied by early sleep disturbances and impairment of olfaction [15]. Moreover, age-related alterations of many basic physiological mechanisms, addressed in this volume (e.g., astroglial aging [17], changes in energy metabolism [8] as well as vascular and hemodynamic properties [2]), likely also affect sleep and sleep/wake processes [4].

Importantly, the brain seems to age in a sex-specific manner, with gender being among the susceptibility predictors for several age-related disorders. AD, for instance, has a higher (1.6–3:1) prevalence in women compared to men, whereas PD has a higher (3.5:1) prevalence in men compared to women [3]. 

Several articles on this issue specifically address gender-specific brain aging and its impact on sensory systems [12, 15], resting-state functional connectivity of brain networks [6], and quality of sleep [4]. Finally, many articles on this special issue compare the aging of brain architecture and function (including sensory processing, cognitive abilities, and sleep) between humans and commonly used laboratory animals (rats and mice) [4, 8, 12–15, 17]. 

The common mechanisms identified in these studies shall enable high-resolution analyses of key cellular/ molecular pathways involved as well as the future development of therapeutics supporting cognitive longevity or even reverting the age-induced impairment of cognition.

the mechanism of cistanche anti-Alzheimer's disease effect

Cistanche is an herb that is commonly used in traditional Chinese medicine. Some studies have suggested that it has potential benefits for treating Alzheimer's disease, although the exact mechanism of action is still being investigated.

One possible way that cistanche could help with Alzheimer's disease is by reducing inflammation in the brain. Inflammation is believed to be a major contributor to the development and progression of Alzheimer's disease, and some studies have found that cistanche extracts can help to reduce inflammation markers in laboratory animals.

Another potential mechanism of action is through its ability to promote the growth of new brain cells. Alzheimer's disease is associated with a loss of brain cells, and some research has suggested that cistanche could help to stimulate the growth of new neurons, which could help to slow the progression of the disease.

Finally, cistanche might also have antioxidant properties, which could help to protect brain cells from damage caused by free radicals. This is important because free radicals are believed to play a role in the development of Alzheimer's disease.

References 

1 Asavapanumas N, Brawek B, Martus P, Garaschuk O (2019) Role of intracellular Ca2+ stores for impairment of visual processing in a mouse model of Alzheimer’s disease. Neurobiol Dis 121:315–326. https://doi.org/10.1016/j.nbd.2018.10.015 

2. Beishon L, Clough RH, Kadicheeni M, Chithiramohan T, Panerai RB, Haunton VJ, Minhas JS, Robinson TG (2021) Vascular and hemodynamic issues of brain aging. Pfugers Arch. https://doi. org/10.1007/s00424-020-02508-9 3. Brawek B, Skok M, Garaschuk O (2021) Changing functional signatures of microglia along the axis of brain aging. Int J Mol Sci 22:1091. https://doi.org/10.3390/ijms22031091 

4. Campos-Beltran D, Marshall L (2021) Changes in sleep EEG with aging in humans and rodents. Pfugers Arch. https://doi.org/10. 1007/s00424-021-02545-y 

5. Garaschuk O, Semchyshyn HM, Lushchak VI (2018) Healthy brain aging: interplay between reactive species, inflammation, and energy supply. Ageing Res Rev 43:26–45. https://doi.org/10. 1016/j.arr.2018.02.003 

6. Jockwitz C, Caspers S (2021) Resting-state networks in the course of aging-differential insights from studies across the lifespan vs. amongst the old. Pfugers Arch. https://doi.org/10.1007/ s00424-021-02520-7 

7. Lerdkrai C, Asavapanumas N, Brawek B, Kovalchuk Y, Mojtahedi N, Olmedillas Del Moral M, Garaschuk O (2018) Intracellular Ca(2+) stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 115:E1279–E1288. https://doi.org/10.1073/pnas.1714409115 

8. Lushchak VI (2021) Interplay between bioenergetics and oxidative stress at normal brain aging. Aging is a result of increasing disbalance in the system's oxidative stress-energy provision. Pfugers Arch. https://doi.org/10.1007/s00424-021-02531-4 

9. Olmedillas Del Moral M, Asavapanumas N, Uzcategui NL, Garaschuk O (2019) Healthy brain aging modifies microglial calcium signaling in vivo. Int J Mol Sci 20:589. https://doi.org/10.3390/ ijms20030589 

10. Olmedillas Del Moral M, Frohlich N, Figarella K, Mojtahedi N, Garaschuk O (2020) Effect of caloric restriction on the in vivo functional properties of aging microglia. Front Immunol 11:750.https://doi.org/10.3389/fmmu.2020.00750 

11. Palop JJ, Mucke L (2016) Network abnormalities and interneuron dysfunction in Alzheimer's disease. Nat Rev Neurosci 17:777–792.https://doi.org/10.1038/nrn.2016.141 

12. Peixoto Pinheiro B, Vona B, Lowenheim H, Ruttiger L, Knipper M, Adel Y (2020) Age-related hearing loss about potassium ion channels in the cochlea and auditory pathway. Pfugers Arch. https://doi.org/10.1007/s00424-020-02496-w 

13. Rivera AD, Chacon-De-La-Rocha I, Pieropan F, Papanikolau M, Azim K, Butt AM (2021) Keeping the aging brain wired: a role for purine signaling in regulating cellular metabolism in oligodendrocyte progenitors. Pfugers Arch. https://doi.org/10.1007/ s00424-021-02544-z 14. Semchyshyn H (2021) Is carbonyl/AGE/RAGE stress a hallmark of brain aging? Pfugers Arch. https://doi.org/10.1007/ s00424-021-02529-y 

15. Tzeng WY, Figarella K, Garaschuk O (2021) Olfactory impairment in men and mice related to aging and amyloid-induced pathology. Pflugers Arch. https://doi.org/10.1007/ s00424-021-02527-0 

16. Vecchio F, Miraglia F, Rodella C, Alu F, Miniussi C, Rossini PM, Pellicciari MC (2020) tDCS efects on brain network properties during physiological aging. Pfugers Arch. https://doi.org/10. 1007/s00424-020-02428-8 

17. Verkhratsky A, Augusto-Oliveira M, Pivoriunas A, Popov A, Brazhe A, Semyanov A (2020) Astroglial asthenia and loss of function, rather than reactivity, contribute to the aging of the brain. Pfugers Arch. https://doi.org/10.1007/s00424-020-02465-3