How to stay younger: have healthy lysosomes

Unfortunately, when cells age, the lysosomes become dysfunctional (6, 7, 8, 9, 10). They are no longer able to digest cellular trash effectively. This has a number of negative secondary effects: 

• The lysosomes accumulate abnormal proteins and lipids. The debris shows up as yellow-brown deposits within the lysosome (lipofuscin - 8).
• The lysosomes can no longer extract amino acids from the cytoplasm; the excess amino acids induce mitochondrial toxicity (7, 9).
• In addition, as the lysosomes amass proteins of senescence and release those into the extracellular fluid, they promote senescence of adjoining cells (3).
• From there, as the lysosomes become more dysfunctional, they break open releasing their content into the cytoplasm, hastening the cell's demise (4, 11).

It's a disheartening outcome. Here we have the cell's recycling systems - the lysosomes - getting larger and larger as the cells age. They gather all the garbage laying around in the cytoplasm, but they lose the ability to dismantle the trash and recycle it. All these cellular waste products become entangled together and solidify into lipofuscin. For example, the neurons of people that are older than 100 years have lipofuscin making up 75% of the total cytoplasm volume (8). How can those neurons breathe?

Why can't the lysosomes digest the junk? Because over time, the lysosome loses the ability to acidify its interior. These small organelles are less able to acidify their insides, leading to an alkaline pH within the lysosome. 

A number of neurodegenerative diseases have been found to result when there is abnormal acid dynamics within the cell's cytoplasm. These include Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis - ALS,  as well as frontotemporal dementias. In fact, aging in experimental animals coincides with declining lysosomal acidity as well as the lysosome's ability to digest macromolecules (6, 9, 10).

Amazingly, losing this acidification capacity is one of the earliest signs of an aging cell. In support of this, studies have revealed impairment of lysosomal acidification before any evidence of overt neuropathology in the cell. In several experimental neurodegenerative scenarios, for example, there is defective lysosomal acidification observed prior to:

• mitochondrial dysfunction
• lysosomal enlargement
• release of lysosomal proteins
• Cytoplasmic acidification
• Evidence of neuro-inflammation 
• the accumulation of abnormally tangled proteins (such as beta-amyloid or tau protein). 

This begs the question whether testing the lysosomes of patients predisposed to neurodegenerative disease can uncover pathology in a preclinical state, when patients are still asymptomatic (6, 7, 9).

An earlier diagnosis of abnormal aging?

Interestingly, skin fibroblast cells from patients with familial Alzheimer's disease as well as patients with Down syndrome both showed slightly higher lysosomal pH values. Researchers are studying probes that can measure lysosomal acidification in the central nervous system using positron emission tomography (PET) imaging.

Other avenues include measuring biomarkers of lysosomal dysfunction in the cerebrospinal fluid or the blood. For example, cathepsin (a lysosomal enzyme) levels are increased in the serum of patients with Alzheimer's disease (11).

This brings up the question whether therapies that help the lysosomes get back their acidification function can help prevent the later stage pathology that takes place in neurodegenerative diseases.

In fact, development of small molecules that target lysosomes and improve their acidification is being actively pursued. One way of doing this is supporting the primary protein that promotes entry of H+ into the lysosome (V-ATPase) (6). Other ways include activating or blocking ion channels that are instrumental in lysosomal acidification. 

For example, Tetrandrine (a drug that inhibits the ion channel TPC2) leads to lysosomal acidification. Transgenic mice with pathological changes of Alzheimer's disease in their brain were treated with Tetrandrine. The drug cleared abnormal protein tangles,  concomitant with acidification of the lysosomes. Furthermore, the drug corrected memory impairment in the mice (12).

Of note, a common therapeutic avenue to longevity is that of intermittent fasting, since calorie restriction has been found to promote healthier aging and longevity. Interestingly, restricting calories decreases the level of amino acids in the lysosome. This allows the lysosome to better regulate its pH levels (9). 

Lysosomal health is key in a cell's overall health 

In summary, the lysosomes are in a key position to regulate the metabolic health of the cell. In doing so, they directly influence the overall longevity of the cell. This is why most anti-aging interventions produce a measurable positive effect on the function of this small and essential organelle (4, 6, 9, 10).