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In vitro geroscience. Screening anti-aging drug combinations for neurodegenerative diseases
* Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School
of Medicine, University of Washington, Seattle, WA, USA.
Email: wladiges@uw.edu
Received: 14 June 2023 / Accepted: 14 June 2023 / Published: 28 June 2023
DOI: 10.31491/APT.2023.06.115
Abstract
Geroscience is based on the concept that therapeutic approaches that work for aging will also work for age-related diseases, including neurodegenerative diseases such as Alzheimer’s disease (AD). Single drugs have been ineffective in treating AD, so it seems reasonable to consider using multiple drugs in combination (cocktails) for a more effective treatment approach. However, initial screening of drug cocktails in animal models is costly and time-consuming. The human neuroblastoma cell line SH-SY5Y has neuronal properties and can be stressed with chemicals or transfected with adeno-associated virus (AAV) Aβ and/or pTau vectors for an in vitro model of neurotoxicity. Drug cocktails can then be easily screened for intervention efficacy compared to each individual drug in the cocktail.
Keywords
Drug cocktails, anti-aging drugs, geroscience, neuroblastoma cell line, Alzheimer’s disease
Alzheimer’s disease (AD) is a common neurodegenerative disease for which no single drug therapy has been
successful. The concept of geroscience is that therapeutic
approaches that work for aging will also work for agerelated diseases, including AD. Therefore, rather than
focusing on testing a single drug, it seems reasonable to
consider using multiple drugs in combination (a cocktail)
for a more effective treatment strategy. However, testing
drug cocktails in animal models is expensive and timeconsuming.
A simple and inexpensive system is needed. In this regard,
Mairuae et al. recently published an article describing the
use of a human neuroblastoma cell line to test the ability of a combination of mulberry fruit and leaf extracts to
prevent hydrogen peroxide-induced cytotoxicity [1]. They
showed that the protective effect was most pronounced
with the extract combination compared to each individual
extract, suggesting an interaction between the two extracts
and that the extract combination hit a broader pathway of
cellular targets.
Their observation reinforces the critical importance of using drug combinations to treat AD. However, this type of
approach has not received the attention it deserves, mainly
because there is still a mystery as to what causes AD, and
in fact there are most likely are multiple causes. The mainstream thinking is that using drug combinations to treat
AD is a shotgun approach and not scientifically sound.
This is counterintuitive to the geroscience concept, which
is based on the underlying principle that if a drug cocktail
is effective in delaying aging, then it will be effective in
delaying the dementia and neuropathology associated with
AD. Our laboratory has recently shown that a combination
of rapamycin, acarbose, and phenylbutyrate is effective in
enhancing resilience to aging in C57BL/6 and HET3 mice
[2]. We also showed that the drug combination delayed
the onset of age-related cognitive impairment [3], suggesting that it would be a promising combination to test for
delaying or preventing AD.
Part of the reluctance to embrace drug combinations for
the treatment of AD may be the high cost and intensive
effort required to conduct such studies in animal models.
An in vitro cell culture system would be ideal for screening drug combinations in a cost-effective and timely
manner, as described by Mairuae et al. [1]. They used
the SH-SY5Y human neuroblastoma cell line, which is
of neuronal origin and exhibits neuronal cell properties
including cytotoxicity influence. To use this cell line to
screen drug combinations for AD, we performed transfections with adeno-associated virus (AAV) vectors containing sequences for Aβ42 and pTau. Drugs that are soluble
in aqueous solutions, such as peptides, are easily tested in
this model system. However, many insoluble drugs can be
solubilized in solvents such as DMSO and still be tested under the right conditions. Since we are not looking for a
specific target, there is no need to use a reporter system.
Instead, we have developed a streamlined immunohistochemistry format with multiple neuropathological markers
as readouts to measure the efficacy of the drug cocktail
compared to each individual drug.
In conclusion, the use of the SH-SY5Y neuroblastoma
cell line is an example of a viable, robust and inexpensive
in vitro system for screening anti-aging drug cocktails as
effective therapeutics for neuronal cell damage associated
with neurodegenerative conditions such as AD. By testing
different combinations of drugs targeting a wider range
of aging pathways, it will be possible to screen candidate
drug cocktails quickly and efficiently, justifying the time
and expense of larger-scale animal studies.
Declarations
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
Warren Ladiges is a member of the editorial board of Aging Pathobiology and Therapeutics. The authors declare that they have no conflicts and were not involved in the journal’s review or decision regarding this manuscript.
References
1. Mairuae N, Palachai N, & Noisa P. The neuroprotective effects of the combined extract of mulberry fruit and mulberry leaf against hydrogen peroxide-induced cytotoxicity in SH-SY5Y Cells. BMC Complement Med Ther, 2023, 23(1): 117-133. [Crossref]
2. Jiang Z, Wang J, Imai D, Snider T, Klug J, Mangalindan R, et al. Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice. Sci Rep, 2022, 12(1): 7300-7312. [Crossref]
3. Zhou J, Qianpei H, & Warren L. A cocktail of rapamycin, acarbose and phenylbutyrate prevents age-related cognitive decline in mice by altering aging pathways. bioRxiv, 2022: 2022.2009.2007.506968. [Crossref]