What Salient Changes Take Place in Human Beings During Aging?

The most striking physiologically important changes in human abilities across our life span are the LINEAR DECLINE in functional capacities of our abilities to have good organ function and physical strength. This is coupled with a gradual increase in oxidative (free radical damage) to the proteins in our cells and lipids(fats) in our cellular membranes. These changes occur across the midlife period, only later when we are much less competent at protection and repair do we see huge increases in damage to some of our genetic material. Our genetic material is made of DNA, mostly located in the central nucleus of our cells or the minor amounts in our energy production organelles within our cells called 'mitochondria'. Major DNA damage takes place in these mitochondrial DNA molecules with late age in humans. We will focus on these gradual changes in midlife as retarding them is most likely to extend our healthy period of life.
We suffer a general LINEAR DECLINE
in all organ and work output capabilities across human life. This is shown in the lower graph of decline in function relative to the 30 year old level. Note that the conserved (unchanged or horizontal  fasting glucose level is only for individuals who have maintained trim body weight and have no progression toward diabetes or metabolic syndrome  and insulin resistance (rising blood sugar, etc.). Other indications like our Nerve Conduction Velocity, Cardiac Index (heart  capability to pump blood), our maximum blood flow (Vital Capacity), our Maximal Breathing Capacity, and finally our Maximal Work capacity or Oxygen uptake capability all decline LINEARLY over the midlife period.

Another important decline over the course of our life time is the increase of oxidation of both membrane lipids and cellular proteins. Oxidation means that some reactive component (a free radical=a molecule with an unpaired reactive electron) or our metabolism or the environment reacts to and damages some membrane lipid or protein in our body. We will be much more detailed about oxidation in the ANTIOXIDANTS section.

The gradual increase in oxidized proteins and membrane lipids seen over the course of aging is most striking for proteins. A young man has perhaps 10% oxidatively damaged  cellular proteins, while a 70 year old man has some 50% of his proteins oxidatively damaged (Protein Modifications with Aging  Levine, RL & Stadtman, ER  IN: Handbook of the Biology of Aging (4th Ed.) 184-197 (1996)). 

Ability of the old to function well and especially to handle unusual stresses (infections, colds, etc.) is extremely decreased with such a high rate of oxidative damage. Our various body systems ability to increase functional output by some 5 fold in youth drops continuously with age. On can think of this as a generalized "Reserve Capacity" (Reserve capacity) that you can call upon output under stress conditions. Humans often need to increase various organ function levels in the face of some insult or infection or mere stressful conditions. Older humans are thus less able to resist the insults and diseases of late life.

A similar process but less extreme decay is seen in cellular membrane damage across life span. Membranes are constantly repaired through all of life as they are critical to maintenance of the physical structure of our cells and their ability to receive external signals as well as exchange nutrients in and our wastes out of our cells. What makes cellular membranes so easily damaged (and in constant need of repair) is the fact that a single free radical can damage many membrane lipids in a cascade or chain reaction of damage that must be repaired rapidly.  We will cover each of these in more detail in the ANTIOXIDANTS section.

Over the length of our life span, there is a slow gradual increase in the prevalence of these damaging free radical molecules. This increase leads to damage to important biological molecules with higher damage later in life.  A young man has some 10% of his cellular protein oxidatively damaged in this free radical process, but a 70 year old man has about 50% of his cellular proteins damaged (Levine, RL & Stadtman, ER  IN: Handbook of the Biology of Aging (4th Ed.) 184-197 (1996)). This is a failure of the process of AUTOPHAGY (breaking down or catabolism of  damaged molecules) described in HOW & WHY? Section that we attributed to elevated TOR gene levels and an absence of sufficient fasting period to activate AUTOPHAGY. The underlying cause of the damage to these proteins is free radical attack. From the 1950’s this gradual increase in free racial creation and consequent damage was believed to be ”the predominant” (but not only) gradual aging process that was principally responsible for our aging and death. 

Because lipids are a major component of living organisms and probably the first easy target of free radicals once they are produced, lipid peroxidation might play an important role in initiating and/or mediating some aspects of the aging process. It has been widely demonstrated that there is an age-associated increase in the steady-state concentrations of lipid peroxidation products. Lipid peroxidation and the aging process.  Praticò D.  Sci Aging Knowledge Environ. 2002 Dec 18;2002(50):re5.   http://www.ncbi.nlm.nih.gov/pubmed/14603026 .

As you can see from the above graph, membrane lipids under go a gradual elevation of free radical damage over the life time that impairs their cellular function. Membrane lipids are of particular concern because these damaging events can have a single free radical molecule onset and go on to have many to 10’s of damaged membrane lipids. This process of amplified or free radical “chain” reaction as a cyclical processes that can generate a huge increase in the levels of oxidatively damaged biologically important unsaturated membrane lipid molecules. This can also spread further free radical damage to other areas of the cell. Our unsaturated membrane lipids are particularly prone to this radical chain reaction. Our body is always repairing the “on going”  damage.

• Free Radical + UnsatMembraneLipid(R) -> (stable former FR) +  •R (damaged membrane lipid as free radical)

• R + R -> Damaged R + •R

repeat last step many to tens of times- get a chain reaction

Similar, but usually less extensive cyclical processes can also occur in the water soluble material of the cell. Many other free radical damages are much more limited to a single target (rather than a chain reaction). If a free radical damages a protein in your cell by a process of adding an oxygen where it does not belong (for  non-sulfur amino acids in a protein), your cell must retire (break into amino acids for re-synthesis) that protein and build it again.  This is a relatively  expensive process energetically.

If a free radical was to damage DNA (our master cellular information source for creating various proteins), we could  suffer a permanent change in the coding information that was “hit”. These DNA mutations are not always fixable, despite a very strong effort of our cells to repair damage. What is pleasing to know is that our nuclear genes (the central cellular DNA warehouse inside a protected organelle called the nucleus) are relatively protected against much damage over most of our life time. Only very late in life does the rate of this “nuclear” DNA damage greatly increase. This remarkable preservation of our nuclear DNA is seen in the various cloning experiments (e.g.. Dolly the sheep) where an adult nucleus (DNA) was placed in an enucleated oocyte (DNA nucleus removed) and then implanted in another sheep for embryonic development to a viable live birth. Dolly the genetically identical off spring was viable and lived most of the duration of a normal sheep’s life. This is in spite of some 90 cell doublings in this process of going from a single cell to the whole adult sheep.

In animal cells,much of the total cellular free radical creation process occurs in the energy producing intracellular organelle called the mitochondria. This mitochondria produces most of our available cellular energy. In the mitochondria, metabolism of various food related glucose, fats, protein residues occurs by a controlled complex stepwise process where food is stripped of chemical energy and then combine with O2 to form CO2 and water. In the process of gaining this energy, some free radicals are created in the mitochondria. These free radicals are at highest concentration inside the mitochondria, The mitochondria also has a small residual “bacterial strand of necessary DNA” encoding genes needed to produce the high amounts of ATP energy. that our cells need. There is a low level of damage to this “bacterial strand of necessary DNA” for most of our life time that very slowly increases until it massively increases in late human life. This is well before any such major increase in damage in our nuclear DNA. Part of the reason for this is the lesser enzymatic repair in the mitochondria and part is due the absence of sufficient AUTOPHAGY to retire old defective (poor energy producing) mitochondria. We covered AUTOPHAGY in the HOW AND WHY section with respect to protein. This lack of AUTOPHAGY of defective (poor energy producing) mitochondria is also a consequence of elevated TOR gene levels. Unfortunately, the mitochondria has much less protection than our central nucleus DNA storehouse, so it accumulates more permanent  radical damage and deletions than the DNA in our nucleus. Eventually, a larger and larger fraction of our mitochondria are not good energy producers and the burden is on the remaining functional mitochondria. Below is a chart of the occurrence of DNA damage to mitochnondrial DNA over the human life span. One obvious solution to this is the use of the compounds DMAE (dimethylaminoethanol) or  Centrophenoxine (a drug containing DMAE that easily gets in to the brain). These will be covered in the SUPPLEMENTS section.

Attempts to gain a longer life span by boosting protection against this slowly rising free radical damage process were done by adding to the diet EXOGENOUS (not produced in the body) antioxidants. These attempts have largely been failures. This was tried by adding natural antioxidants like Vitamins C, E, and a group of plant compounds  called carotenoids (red to yellow colored plant pigments that intercept specific types of free radicals). After this failure, far stronger EXOGENOUS antioxidants were tried in the same process with the similar results. What was gained by these high antioxidant experiments was a realization that many of the diseases of aging were pushed further out in  time, but life spans were not  increased. We need to get enough antioxidants to prevent needless damage and also to put off as much as possible needless diseases of age. As we will learn later in the LONGEVITY section , the combination of antioxidants and natural anti-inflammatories adn better glucose control is a much better approach. It is extremely probably that the extension of maximal and average life span in Calorie Restricted animals is due to better maintenance related to regular periods of fasting that recycle damaged molecules and also recruit stem cells to replace and rejuvenate organs and tissues. So far, this can only be accomplished by fasting ! Better maintenance should also delay the mitochondrial damage seen above to a later period for a LONGER HEALTHY LIFE.